Publications by authors named "Yizhou Zou"

40 Publications

Innate lymphoid cells are double-edged swords under the mucosal barrier.

J Cell Mol Med 2021 Sep 10;25(18):8579-8587. Epub 2021 Aug 10.

Department of Physiology, School of Basic Medicine Science, Central South University, Changsha, China.

As the direct contacting site for pathogens and allergens, the mucosal barrier plays a vital role in the lungs and intestines. Innate lymphoid cells (ILCs) are particularly resident in the mucosal barrier and participate in several pathophysiological processes, such as maintaining or disrupting barrier integrity, preventing various pathogenic invasions. In the pulmonary mucosae, ILCs sometimes aggravate inflammation and mucus hypersecretion but restore airway epithelial integrity and maintain lung tissue homeostasis at other times. In the intestinal mucosae, ILCs can increase epithelial permeability, leading to severe intestinal inflammation on the one hand, and assist mucosal barrier in resisting bacterial invasion on the other hand. In this review, we will illustrate the positive and negative roles of ILCs in mucosal barrier immunity.
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http://dx.doi.org/10.1111/jcmm.16856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8435454PMC
September 2021

The leukocyte immunoglobulin-like receptor gp49B1, coexpressed with c-Kit, modulates hematopoiesis and B cell leukemia development.

Biochem Biophys Res Commun 2021 Aug 4;565:72-78. Epub 2021 Jun 4.

Department of Immunology, School of Basic Medical Science, Central South University, Changsha City, Hunan Province, China. Electronic address:

A better understanding of cell-intrinsic factors involved in regulating stem cells and cancer cells will help advance stem cell applications and cancer cell treatment. Previously, we showed that leukocyte immunoglobulin-like receptor B2 (LILRB2) and its mouse ortholog, paired immunoglobulin-like receptor B (PIRB), promote blood stem cell and leukemia development. Another unique mouse paralog to PIRB called gp49B1 was also discovered. However, the roles of gp49B1 in hematopoietic stem cells and leukemia development are largely unknown. Here, we found that gp49B1 is expressed on LSK cells of mouse neonatal hematopoietic organs and is positively correlated with c-Kit expression. However, in noncompetitive and competitive repopulation assays, neonatal splenic gp49B1-positive and c-Kit-highly expressed LSK cells exhibited poor engraftment potential and lymphoid lineage bias. Moreover, in a mouse N-Myc-induced precursor B-acute lymphoblastic leukemia (pre-B ALL) model, we found that gp49B1 deficiency or low levels of c-Kit led to a delay in leukemia development. Together, our results suggest that gp49B1 expressed on hematopoietic progenitor cells supports hematopoietic and leukemia development.
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http://dx.doi.org/10.1016/j.bbrc.2021.05.090DOI Listing
August 2021

Glycemic deviation index: a novel method of integrating glycemic numerical value and variability.

BMC Endocr Disord 2021 Mar 19;21(1):52. Epub 2021 Mar 19.

Department of Endocrinology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, 324 Jing 5 Road, Jinan, 250021, China.

Background: There are many continuous blood glucose monitoring (CGM) data-based indicators, and most of these focus on a single characteristic of abnormal blood glucose. An ideal index that integrates and evaluates multiple characteristics of blood glucose has not yet been established.

Methods: In this study, we proposed the glycemic deviation index (GDI) as a novel integrating characteristic, which mainly incorporates the assessment of the glycemic numerical value and variability. To verify its effectiveness, GDI was applied to the simulated 24 h glycemic profiles and the CGM data of type 2 diabetes (T2D) patients (n = 30).

Results: Evaluation of the GDI of the 24 h simulated glycemic profiles showed that the occurrence of hypoglycemia was numerically the same as hyperglycemia in increasing GDI. Meanwhile, glycemic variability was added as an independent factor. One-way ANOVA results showed that the application of GDI showed statistically significant differences in clinical glycemic parameters, average glycemic parameters, and glycemic variability parameters among the T2D groups with different glycemic levels.

Conclusions: In conclusion, GDI integrates the characteristics of the numerical value and the variability in blood glucose levels and may be beneficial for the glycemic management of diabetic patients undergoing CGM treatment.
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http://dx.doi.org/10.1186/s12902-021-00691-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7976707PMC
March 2021

Genomic characterization of MICA gene using multiple next generation sequencing platforms: A validation study.

HLA 2020 10 21;96(4):430-444. Epub 2020 Aug 21.

Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

We have developed a protocol regarding the genomic characterization of the MICA gene by next generation sequencing (NGS). The amplicon includes the full length of the gene and is about 13 kb. A total of 156 samples were included in the study. Ninety-seven of these samples were previously characterized at MICA by legacy methods (Sanger or sequence specific oligonucleotide) and were used to evaluate the accuracy, precision, specificity, and sensitivity of the assay. An additional 59 DNA samples of unknown ethnicity volunteers from the United States were only genotyped by NGS. Samples were chosen to contain a diverse set of alleles. Our NGS approach included a first round of sequencing on the Illumina MiSeq platform and a second round of sequencing on the MinION platform by Oxford Nanopore Technology (ONT), on selected samples for the purpose of either characterizing new alleles or setting phase among multiple polymorphisms to resolve ambiguities or generate complete sequence for alleles that were only partially reported in the IMGT/HLA database. Complete consensus sequences were generated for every allele sequenced with ONT, extending from the 5' untranslated region (UTR) to the 3' UTR of the MICA gene. Thirty-two MICA sequences were submitted to the IMGT/HLA database including either new alleles or filling up the gaps (exonic, intronic and/or UTRs) of already reported alleles. Some of the challenges associated with the characterization of these samples are discussed.
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http://dx.doi.org/10.1111/tan.13998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589345PMC
October 2020

Airway epithelial integrin β4 suppresses allergic inflammation by decreasing CCL17 production.

Clin Sci (Lond) 2020 07;134(13):1735-1749

Department of Physiology, School of Basic Medicine Science, Central South University, Changsha, Hunan, China.

Airway epithelial cells (AECs) play a key role in asthma susceptibility and severity. Integrin β4 (ITGB4) is a structural adhesion molecule that is down-regulated in the airway epithelium of asthma patients. Although a few studies hint toward the role of ITGB4 in asthmatic inflammation pathogenesis, their specific resultant effects remain unexplored. In the present study, we determined the role of ITGB4 of AECs in the regulation of Th2 response and identified the underpinning molecular mechanisms. We found that ITGB4 deficiency led to exaggerated lung inflammation and AHR with higher production of CCL17 in house dust mite (HDM)-treated mice. ITGB4 regulated CCL17 production in AECs through EGFR, ERK and NF-κB pathways. EFGR-antagonist treatment or the neutralization of CCL17 both inhibited exaggerated pathological marks in HDM-challenged ITGB4-deficient mice. Together, these results demonstrated the involvement of ITGB4 deficiency in the development of Th2 responses of allergic asthma by down-regulation of EGFR and CCL17 pathway in AECs.
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http://dx.doi.org/10.1042/CS20191188DOI Listing
July 2020

Tumor-Derived Soluble MICA Obstructs the NKG2D Pathway to Restrain NK Cytotoxicity.

Aging Dis 2020 Feb 1;11(1):118-128. Epub 2020 Feb 1.

1Department of Immunology, Basic Medical School of Central South University, Changsha, Hunan, China.

The natural killer group 2D (NKG2D) receptor and its ligands play important roles in immune surveillance. In this study, we observed that the average serum soluble MICA (sMICA) concentration of 174 hepatocellular carcinoma (HCC) patients was significantly higher than that in 80 healthy subjects (602.17 ± 338.15 vs. 72.26 ± 87.88 pg/ml, t = 3.107, P=0.002). The levels of serum sMICA in 44 HCC patients with initial levels above 400 pg/ml declined significantly after surgical removal of the liver cancer tissue (P<0.001). Moreover, the mean survival time of HCC patients who had sMICA above 400 pg/ml was significantly shorter than that HCC patients with lower sMICA levels (P<0.001). Using the reporter cell line (NKG2D-2B4) in which activation of the NKG2D receptor pathway results in GFP expression based on the stimulation of immobilized rMICA, we showed that the number of GFP-expressing cells decreased sharply in presence of sMICA. Upon adding sMICA, the release of cytokines IFN-γ, TNF-α, and IL-8 by NK cell line (NKL) under stimulation of immobilized rMICA was blocked. Using MICA-expressing cells as the target cells, we observed that about 80% of target cells were killed by NKL at E:T of 10:1, but in presence of sMICA serum of HCC patients, the dead target cells were reduced to 30.8%. Compared in presence of sMICA serum from HCC patients, there were 63.7% of target cells dead (p=0.043). Thus, our data suggested that sMICA obstructs the activation of NKG2D pathway to protect tumor cells from NK cell-mediated cytotoxicity.
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http://dx.doi.org/10.14336/AD.2019.1017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6961768PMC
February 2020

Airway epithelial ITGB4 deficiency in early life mediates pulmonary spontaneous inflammation and enhanced allergic immune response.

J Cell Mol Med 2020 03 22;24(5):2761-2771. Epub 2020 Jan 22.

Department of Physiology, School of Basic Medicine Science, Central South University, Changsha, China.

Lung immune responses to respiratory pathogens and allergens are initiated in early life which will further influence the later onset of asthma. The airway epithelia form the first mechanical physical barrier to allergic stimuli and environmental pollutants, which is also the key regulator in the initiation and development of lung immune response. However, the epithelial regulation mechanisms of early-life lung immune responses are far from clear. Our previous study found that integrin β4 (ITGB4) is decreased in the airway epithelium of asthma patients with specific variant site. ITGB4 deficiency in adult mice aggravated the lung Th2 immune responses and enhanced airway hyper-responsiveness (AHR) with a house dust mite (HDM)-induced asthma model. However, the contribution of ITGB4 to the postnatal lung immune response is still obscure. Here, we further demonstrated that ITGB4 deficiency following birth mediates spontaneous lung inflammation with ILC2 activation and increased infiltration of eosinophils and lymphocytes. Moreover, ITGB4 deficiency regulated thymic stromal lymphopoietin (TSLP) production in airway epithelial cells through EGFR pathways. Neutralization of TSLP inhibited the spontaneous inflammation significantly in ITGB4-deficient mice. Furthermore, we also found that ITGB4 deficiency led to exaggerated lung allergic inflammation response to HDM stress. In all, these findings indicate that ITGB4 deficiency in early life causes spontaneous lung inflammation and induces exaggerated lung inflammation response to HDM aeroallergen.
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http://dx.doi.org/10.1111/jcmm.15000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7077534PMC
March 2020

Strategies to achieve immune tolerance in allogeneic solid organ transplantation.

Transpl Immunol 2020 02 23;58:101250. Epub 2019 Oct 23.

Xiangya School of Medicine, Central South University, Changsha 410000, Hunan, China. Electronic address:

Organ transplantation is an effective way to treat many end-stage diseases. In order to overcome post-transplant rejection, immunosuppressive agents have been widely used, but the long-term survival of transplanted organs still has not been achieved in the clinic. For decades, tolerance is the "holy grail" that transplant immunologists have longed for. The well-known approaches to induce immune tolerance are through adoptively transferred regulatory T cells and achieving chimeric states. In addition, there are a variety of promising potential strategies, including costimulatory blockade, regulating differentiation of immune cell subgroups, adoptive infusion of immunoregulatory cells, using apoptotic cells to induce tolerance, stem cell regenerative medicine to reconstitute tissue and organs, helminthic therapy, using exosomes carrying phagocytic antigen and phagocytic vesicles to induce tolerance, and blocking CD3 and targeted clearance of memory T cells. In this paper, we review the current developments and the potential of these strategies to achieve transplantation tolerance.
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http://dx.doi.org/10.1016/j.trim.2019.101250DOI Listing
February 2020

Identification of the first case of SFTSV infection in the Hunan Province of China and epidemiological surveillance in the locality.

Ticks Tick Borne Dis 2019 02 13;10(2):454-461. Epub 2018 Nov 13.

School of Basic Medical Science, Central South University, Hunan Province, People's Republic of China. Electronic address:

This study reports the etiological identification, clinical diagnosis, and the results of the local epidemiological surveillance of the first case of severe fever with thrombocytopenia syndrome virus (SFTSV) infection in 2014 in Hunan Province, China. The infected patient was isolated and closely monitored. The virus is a member of the Bunyaviridae sandfly family and is characterized by real-time PCR, electron microscopy, immunofluorescence, and whole-genome sequencing. We also detected IgG and IgM antibodies against SFTSV among the local human population and domestic animals in a serological surveillance. Prevalence of SFTSV-specific antibodies was monitored in the local population for two years after the identification of the first SFTS case. Approximately 5% (4/77) of the people who had direct contact with the patient were seropositive, which is significantly higher than the seropositivity of the general local population [1.57% (44/2800), P < 0.05]. Furthermore, the percentage of the general population who were seropositive was higher in 2015 than in 2014 (χ2 = 7.481, P = 0.006). The epidemiological investigation found that the SFTSV is epidemic in goats, cattle, and chickens in Hunan Province. The risk of infection of domestic animals can be minimized by feeding in pens rather than allowing foraging.
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http://dx.doi.org/10.1016/j.ttbdis.2018.11.011DOI Listing
February 2019

LILRB4 signalling in leukaemia cells mediates T cell suppression and tumour infiltration.

Nature 2018 10 17;562(7728):605-609. Epub 2018 Oct 17.

Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA.

Immune checkpoint blockade therapy has been successful in treating some types of cancer but has not shown clinical benefits for treating leukaemia. This result suggests that leukaemia uses unique mechanisms to evade this therapy. Certain immune inhibitory receptors that are expressed by normal immune cells are also present on leukaemia cells. Whether these receptors can initiate immune-related primary signalling in tumour cells remains unknown. Here we use mouse models and human cells to show that LILRB4, an immunoreceptor tyrosine-based inhibition motif-containing receptor and a marker of monocytic leukaemia, supports tumour cell infiltration into tissues and suppresses T cell activity via a signalling pathway that involves APOE, LILRB4, SHP-2, uPAR and ARG1 in acute myeloid leukaemia (AML) cells. Deletion of LILRB4 or the use of antibodies to block LILRB4 signalling impeded AML development. Thus, LILRB4 orchestrates tumour invasion pathways in monocytic leukaemia cells by creating an immunosuppressive microenvironment. LILRB4 represents a compelling target for the treatment of monocytic AML.
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http://dx.doi.org/10.1038/s41586-018-0615-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6296374PMC
October 2018

NK cell-mediated anti-leukemia cytotoxicity is enhanced using a NKG2D ligand MICA and anti-CD20 scfv chimeric protein.

Eur J Immunol 2018 10 16;48(10):1750-1763. Epub 2018 Aug 16.

Department of Physiology, UT Southwestern Medical Center at Dallas, TX, USA.

NK cells are important innate cytotoxic lymphocytes that have potential in treatment of leukemia. Engagement of NKG2D receptor on NK cells enhances the target cytotoxicity. Here, we produced a fusion protein consisting of the extracellular domain of the NKG2D ligand MICA and the anti-CD20 single-chain variable fragment (scfv). This recombinant protein is capable of binding both NK cells and CD20 tumor cells. Using a human NKG2D reporter cell system we developed, we showed that this fusion protein could decorate CD20 tumor cells with MICA extracellular domain and activate NK through NKG2D. We further demonstrated that this protein could specifically induce the ability of a NK cell line (NKL) and primary NK cells to lyse CD20 leukemia cells. Moreover, we found that downregulation of surface HLA class I expression in the target cells improved NKL-mediated killing. Our results demonstrated that this recombinant protein specifically lyses leukemia cells by NK cells, which may lead to development of a novel strategy for treating leukemia and other tumors.
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http://dx.doi.org/10.1002/eji.201847550DOI Listing
October 2018

Spheroid-cultured human umbilical cord-derived mesenchymal stem cells attenuate hepatic ischemia-reperfusion injury in rats.

Sci Rep 2018 02 6;8(1):2518. Epub 2018 Feb 6.

Department of Organ Transplantation, Xiangya Hospital, Central South University, Changsha, 410078, China.

Mesenchymal stem cell (MSC) transplantation is a promising treatment for ischemia-reperfusion injury (IRI). However, its effects on hepatic IRI were not consistent in the previous studies. 3D spheroid-cultured MSCs enhance their production of trophic and anti-inflammatory properties, but their effects on hepatic IRI remain unclear. In this study, we compared the 3D spheroid-cultured human umbilical derived MSCs (3D UC-MSCs) with 2D-cultured UC-MSCs (2D UC-MSCs) on treating hepatic IRI. The RNA sequencing data showed that suppression of cell mitosis, response to hypoxia, inflammation, and angiogenesis were the top genetic changes in 3D UC-MSCs compared with 2D UC-MSCs. Although both pro-inflammatory and anti-inflammatory genes were upregulated in the 3D UC-MSCs, the mRNA and protein of an RNase (ZC3H12A), which turnovers the mRNA of pro-inflammatory genes at the post-transcript level, were significantly upregulated in 3D UC-MSCs. 3D UC-MSCs reduced the secretion of many chemokines and growth factors, but increased the secretion of vascular endothelial growth factor. Compared with the vehicle and 2D UC-MSCs, 3D UC-MSCs significantly reduced hepatic IRI in rats, based on the plasma aminotransferase levels, liver damage scores, neutrophil infiltration, hepatocyte apoptosis and expression of inflammation-associated genes. These findings suggest that 3D UC-MSCs therapy is a promising treatment for hepatic IRI.
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http://dx.doi.org/10.1038/s41598-018-20975-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5802716PMC
February 2018

ITGB4 is essential for containing HDM-induced airway inflammation and airway hyperresponsiveness.

J Leukoc Biol 2018 05 2;103(5):897-908. Epub 2018 Feb 2.

Departments of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China.

Airway epithelial cells play a significant role in the pathogenesis of asthma. Although the structural and functional defects of airway epithelial cells have been postulated to increase asthma susceptibility and exacerbate asthma severity, the mechanism and implication of these defects remain uncertain. Integrin β4 (ITGB4) is a structural adhesion molecule that is downregulated in the airway epithelium of asthma patients. In this study, we demonstrated that ITGB4 deficiency leads to severe allergy-induced airway inflammation and airway hyper-responsiveness (AHR) in mice. After house dust mite (HDM) challenge, epithelial cell-specific ITGB4-deleted mice showed increased lymphocyte, eosinophil, and neutrophil infiltration into lung compared with that of the wild-type mice. ITGB4 deficiency also resulted in increased expression of the Th2 cytokine IL-4, IL-13, and the Th17 cytokine IL-17A in the lung tissue and in the T cells after HDM challenge. The aggravated inflammation in ITGB4 defect mice was partly caused by enhanced disrupted epithelial barrier integrity after HDM stress, which induced the increased thymic stromal lymphopoietin secretion from airway epithelial cells. This study therefore demonstrates that ITGB4 plays a pivotal role in containing allergen-mediated lung inflammation and airway hyper-responsiveness in allergic asthma.
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http://dx.doi.org/10.1002/JLB.3A1017-411RRDOI Listing
May 2018

Polymorphism of keratin 1 associates with systemic lupus erythematosus and systemic sclerosis in a south Chinese population.

PLoS One 2017 13;12(10):e0186409. Epub 2017 Oct 13.

Department of Immunology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China.

Both systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) diseases are related to the genetic and environmental factors, causing damage to the skin. The mutations of keratin 1 gene (KRT1) were reported to associate with skin diseases. The single-nucleotide polymorphism (SNP, rs14024) and the indel polymorphism (cds-indel, rs267607656), consisting mostly of the common haplotypes and could be used for genotyping of KRT1. We used the PCR with sequence specific primers (PCR-SSP) to determine the genotype of KRT1 in 164 SLE, 99 SSc patients, and 418 healthy controls. The results showed that the mutant with G at SNP rs14024 was associated with the high risk to SLE (p = 6.48×10-5) and SSc (p = 8.75×10-5), while the deletion allele at rs267607656 was associated with the low risk to SSc (p = 4.89×10-4) comparing to the normal controls. Haplogenotype, Del-/MU+ was associated with high susceptibility to SLE (OR = 1.87, p = 0.001) and SSc (OR = 2.29, p = 2.34×10-4). In contrast, the Haplogenotype Del+/MU- was associated with resistance to SLE (OR = 0.35, p = 6.24×10-5) and SSc (OR = 0.34, p = 0.001). This study demonstrates that the variations in KRT1 and the specific polymorphism of KRT1 in this Chinese Han population are associated with autoimmune diseases SLE and SSc. Typing KRT1 might be helpful to identify SLE and SSc patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0186409PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5640249PMC
October 2017

Analysis of Sera of Recipients with Allograft Rejection Indicates That Keratin 1 Is the Target of Anti-Endothelial Antibodies.

J Immunol Res 2017 7;2017:8679841. Epub 2017 Feb 7.

Department of Immunology, Xiangya School of Medicine, Central South University, Hunan 410008, China; The Cooperative Innovation Center of Engineering and New Products for Developmental Biology of Hunan Province, Hunan 410006, China.

Anti-endothelial cell antibodies (AECAs) are usually directed against the surface antigens on the vascular endothelial cells. Clinical studies suggest a pathogenic role for nonhuman leukocyte antigen in antibody-mediated rejection; however, the antigens on the donor vascular endothelium that serve as the first-line targets for an immune response during allograft rejection have not been fully identified. Here, we used immunoprecipitation and mass spectrometry to identify antigens from the sera of kidney transplant recipients who were experiencing antibody-mediated rejection. Keratin 1 (KRT1) was identified as a novel antigenic target expressed on endothelial cells. To validate our finding, we produced recombinant proteins representing the three most common alleles of KRT1. The serum used for immunoprecipitation showed a strong reaction to KRT1 recombinants in western blot and ELISA. In the kidney transplant cohort, more AECA-positive recipients than AECA-negative recipients had KRT1 antibodies (32.2% versus 11.9%, = 0.002). Sera from 255 renal recipients were tested by ELISA. Of the 77 recipients with deteriorating graft function (serum creatinine > 120 mol/L), 23 had anti-KRT1 antibodies. KRT1-IgG positivity was, therefore, associated with a higher risk of kidney transplant rejection (29.9% (23/77) versus 16.9% (30/178), = 0.0187). A better understanding of this antigenic target will improve long-term allograft survival.
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http://dx.doi.org/10.1155/2017/8679841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5318619PMC
March 2017

Cytokine response to Hantaan virus infection in patients with hemorrhagic fever with renal syndrome.

J Med Virol 2017 07 10;89(7):1139-1145. Epub 2017 Feb 10.

Department of Immunology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China.

Hantaan virus (HTNV) infection of the human body causes a severe acute infectious disease known as hemorrhagic fever renal syndrome (HFRS). The aim of this study was to correlate patient cytokine profiles to HFRS severity. In this study, we discuss the clinical significance of evaluating HFRS treatment outcomes using cytokine information. The levels of 18 cytokines were quantitatively determined in three groups: 34 HTNV IgM+ cases, 63 HTNV IgM- negative cases, and 78 healthy volunteers. The level of 14 serum cytokines were higher in the patient group than that in the healthy control group. In the 34 HTNV IgM+ patient sera, a set of 27 cytokines was further assessed. The cytokines of TNF-β, IL-1ra, and IL-6 were detected at higher level in the IgM+ group than that in the IgM- group. The deterioration of HFRS was accompanied with multiple cytokines increased, such as IL-1ra, IL-12p70, IL-10, IP-10, IL-17, IL-2, and IL-6. Our data indicate that serum cytokine levels are associated with the progression of HFRS.
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http://dx.doi.org/10.1002/jmv.24752DOI Listing
July 2017

Fasting selectively blocks development of acute lymphoblastic leukemia via leptin-receptor upregulation.

Nat Med 2017 01 12;23(1):79-90. Epub 2016 Dec 12.

Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

New therapeutic approaches are needed to treat leukemia effectively. Dietary restriction regimens, including fasting, have been considered for the prevention and treatment of certain solid tumor types. However, whether and how dietary restriction affects hematopoietic malignancies is unknown. Here we report that fasting alone robustly inhibits the initiation and reverses the leukemic progression of both B cell and T cell acute lymphoblastic leukemia (B-ALL and T-ALL, respectively), but not acute myeloid leukemia (AML), in mouse models of these tumors. Mechanistically, we found that attenuated leptin-receptor (LEPR) expression is essential for the development and maintenance of ALL, and that fasting inhibits ALL development by upregulation of LEPR and its downstream signaling through the protein PR/SET domain 1 (PRDM1). The expression of LEPR signaling-related genes correlated with the prognosis of pediatric patients with pre-B-ALL, and fasting effectively inhibited B-ALL growth in a human xenograft model. Our results indicate that the effects of fasting on tumor growth are cancer-type dependent, and they suggest new avenues for the development of treatment strategies for leukemia.
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http://dx.doi.org/10.1038/nm.4252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6956990PMC
January 2017

Acute Antibody-Mediated Rejection in Presence of MICA-DSA and Successful Renal Re-Transplant with Negative-MICA Virtual Crossmatch.

PLoS One 2015 29;10(5):e0127861. Epub 2015 May 29.

HLA Histocompatibility Laboratory, Department of Immunology, Xiangya School of Medicine, Center South University, Changsha, Hunan, China; The Cooperative Innovation Center of Engineering and New Products for Developmental Biology of Hunan Province, Changsha, Hunan, China.

The presence of donor-specific alloantibodies (DSAs) against the MICA antigen results in high risk for antibody-mediated rejection (AMR) of a transplanted kidney, especially in patients receiving a re-transplant. We describe the incidence of acute C4d+ AMR in a patient who had received a first kidney transplant with a zero HLA antigen mismatch. Retrospective analysis of post-transplant T and B cell crossmatches were negative, but a high level of MICA alloantibody was detected in sera collected both before and after transplant. The DSA against the first allograft mismatched MICA*018 was in the recipient. Flow cytometry and cytotoxicity tests with five samples of freshly isolated human umbilical vein endothelial cells demonstrated the alloantibody nature of patient's MICA-DSA. Prior to the second transplant, a MICA virtual crossmatch and T and B cell crossmatches were used to identify a suitable donor. The patient received a second kidney transplant, and allograft was functioning well at one-year follow-up. Our study indicates that MICA virtual crossmatch is important in selection of a kidney donor if the recipient has been sensitized with MICA antigens.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0127861PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4449040PMC
March 2016

IGF binding protein 2 is a cell-autonomous factor supporting survival and migration of acute leukemia cells.

J Hematol Oncol 2013 Oct 8;6(1):72. Epub 2013 Oct 8.

Departments of Physiology and Developmental Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas 75390, TX, USA.

Background: The role of IGF binding protein 2 (IGFBP2) in cancer development is intriguing. Previously we identified IGFBP2 as an extrinsic factor that supports the activity of hematopoietic stem cells (HSCs).

Methods And Results: Here we investigated the role of IGFBP2 in in human leukemia cells and in the retroviral AML1-ETO9a transplantation acute myeloid leukemia (AML) mouse model.

Results: IGFBP2 is highly expressed in certain human AML and acute lymphoblastic leukemia (ALL) cells. Inhibition of expression of endogenous IGFBP2 in human leukemia cells led to elevated apoptosis and decreased migration and, consistently, to decreased activation of AKT and other signaling molecules. We also studied the effects of IGFBP2 knockout in the retroviral AML1-ETO9a transplantation AML mouse model. The deletion of IGFBP2 in donor AML cells significantly decreased leukemia development in transplanted mice. Lack of IGFBP2 resulted in upregulation of PTEN expression and downregulation of AKT activation, in the mouse AML cells. The treatment of IGFBP2 deficient AML cells with a PTEN inhibitor restored the wild-type colony forming ability. The deletion of IGFBP2 also led to decreased AML infiltration into peripheral organs and tissues, suggesting that IGFBP2 is required for the migration of AML cells out of bone marrow.

Conclusion: IGFBP2 is a critical cell-autonomous factor that promotes the survival and migration of acute leukemia cells.
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http://dx.doi.org/10.1186/1756-8722-6-72DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3851819PMC
October 2013

Identification of endothelial cell surface antigens encoded by genes other than HLA. A combined immunoprecipitation and proteomic approach for the identification of antigens recognized by antibodies against endothelial cells in transplant recipients.

Hum Immunol 2013 Nov 24;74(11):1445-52. Epub 2013 May 24.

Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390-8886, United States.

It has been known for some time that transplant recipients may have antibodies to endothelial cells which are not detected on lymphocytes. However, little progress has been made in the analysis of these endothelial antigens. In the present experiments we have attempted to characterize endothelial cell surface antigens to which antibodies were produced during graft rejection. We have used a panel of endothelial cells from umbilical cord veins and found that antibodies with a polymorphic pattern in the panel appeared to correlate with transplant failure of kidney allografts and with the development of transplant-related coronary artery disease (TCAD) in heart transplant recipients. Among 39 patients with kidney allografts, 21 were negative for antibodies to endothelial cells and did well and 18 were positive and had frequent transplant loss (p=0.001). In 18 patients with TCAD and 20 patients of a comparator group without TCAD, association of coronary disease with endothelial cell antibodies was observed (p<0.02). To characterize the endothelial antigens responsible for these serologic reactions we performed immunoprecipitation of reactive antibodies with the corresponding endothelial cell surface antigens, followed by protein identification of the target antigens. Nine proteins were identified in these experiments, 5 were non-polymorphic and appeared to represent autoantigens. Four of the isolated proteins appeared to be polymorphic. They were the Human Major Histocompatibility Complex class I chain-related gene A (MICA), already known to be associated with antibody production and graft failure, human keratin 1, a protein known to be polymorphic and expressed on the surface of endothelial cells, eukaryotic translation initiation factor (EIF) 2A and ErbB3-binding protein 1. The possible role of keratin 1 and the other antigens in allograft rejection requires further investigation.
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http://dx.doi.org/10.1016/j.humimm.2013.05.002DOI Listing
November 2013

Screening for antibodies against MICA by Luminex flow cytometry.

Methods Mol Biol 2012 ;882:279-88

Division of Transplant Immunology, Department of Internal Medicine, UT Southwestern Medical Centre, Dallas, TX, USA.

Antibodies against MICA have been found in organ transplant recipients and were found to be associated with decreased survival of kidney allografts. The MICA antibody screening assay is a Luminex-based solid phase immunoassay designed to detect IgG antibodies binding to beads pre-coated with recombinant preparations of MICA alleles. These beads coated with soluble MICA recombinant proteins including 11 common alleles have been produced in our laboratory and similar preparations have been available from commercial sources. Here, we describe the procedure of MICA antibody screening with a prepared kit, in which all the reagents were optimized and standardized. We also review how to document the quality of single MICA antigen beads using MICA-specific monoclonal antibodies, as well as quality control of the procedure and data analysis.
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http://dx.doi.org/10.1007/978-1-61779-842-9_16DOI Listing
October 2012

High resolution MICA genotyping by sequence-based typing (SBT).

Methods Mol Biol 2012 ;882:183-95

Division of Transplant Immunology, Department of Internal Medicine, UT Southwestern Medical Centre, Dallas, TX, USA.

We have developed a MICA typing method based on polymerase chain reaction (PCR) sequence-based typing and a computer program that determines the polymorphisms and distinguishes the GCT repeats in exon 5. One PCR amplification was performed to obtain templates of 2.2 kb, including exons 2, 3, 4, and 5 of MICA to be sequenced with two forward and two reverse primers. Overlay of nucleotide sequencing signals resulting from presence of different GCT repeats in exon 5 from two different MICA alleles can be identified by a computer program that analyses the combined signal string containing the 35 bases.
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http://dx.doi.org/10.1007/978-1-61779-842-9_11DOI Listing
October 2012

Antibodies against nucleolin in recipients of organ transplants.

Transplantation 2011 Oct;92(7):829-35

Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390-8886, USA.

Background: Patients who reject allografts frequently make strong antibody responses against donor human leukocyte antigens and autoantigens such as vimentin, collagen V, or alpha-tubulin and it has been postulated that autoantibodies may play a role in allograft failure.

Methods: We have used serum from patients who recently rejected an allograft as a source of antibodies in combination with lysates of human umbilical vein endothelial cells as a source of target antigens. Immunoprecipitation and protein identification was performed by mass spectrometry. Recombinant nucleolin was produced and sera were assayed for antibodies by enzyme-linked immunosorbent assay.

Results: Immunoprecipitation with serum WW led to the recognition of the protein nucleolin as a target antigen. By enzyme-linked immunosorbent assay, with recombinant nucleolin (r-nucleolin), the frequency of antibodies to nucleolin were found to be 2.0% in normal subjects, 9.1% in patients waiting for a kidney transplant, 25.5% after irreversible rejection of a kidney allograft, 17.1% after a heart transplant, and 43.8% in heart transplant recipients developing transplant-related coronary artery disease. Antibodies against nucleolin from mice or from transplant patients inhibited endothelial cell proliferation and in vitro capillary-like tube formation and caused apoptosis of human umbilical vein endothelial cells.

Conclusions: Antibodies against nucleolin seem to inhibit and produce apoptosis of proliferating endothelial cells. These antibodies were found in many transplant patients and seemed to be associated with rejection of kidney allografts and with coronary artery disease in heart transplant recipients.
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http://dx.doi.org/10.1097/TP.0b013e31822d0977DOI Listing
October 2011

Major histocompatibility complex class I-related chain A allele mismatching, antibodies, and rejection in renal transplantation.

Hum Immunol 2011 Oct 24;72(10):827-34. Epub 2011 May 24.

Anthony Nolan Research Institute, London, United Kingdom.

Even when kidney allografts are well matched for human leukocyte antigen (HLA) and anti-HLA antibodies are not detected, graft rejection can still occur. There is evidence that some patients who lose their graft have antibodies specific for major histocompatibility complex (MHC) class I-related chain A (MICA) antigens. We investigated whether mismatching MICA alleles associates with MICA antibody production and graft rejection or dysfunction. MICA and HLA antibody screening in 442 recipients was performed, and specificities were confirmed in a subgroup of 227 recipients using single-antigen multiplex technology. For assignment of MICA antibody specificity, we used three independent assays. In addition, MICA alleles of 227 recipients and donors were determined by DNA sequencing. In all, 17 patients (7.5%) had MICA antibodies, and 13 patients (6%) developed MICA donor-specific antibodies (DSA). Multivariate analysis revealed MICA mismatching, as an independent significant factor associated with the presence of MICA antibodies (p = 0.009), and 14 mismatched MICA residues significantly correlated with MICA antibody production. MICA and HLA antibodies significantly associated with acute rejection (AR) and MICA DSA and HLA DSA correlated with decreased graft function by univariate and multivariate analysis. We conclude that mismatching for MICA epitopes in renal transplantation is a mechanism leading to production of MICA antibodies that associate with AR and graft dysfunction.
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http://dx.doi.org/10.1016/j.humimm.2011.05.004DOI Listing
October 2011

Antibodies against major histocompatibility complex class I-related chain A in transplant recipients.

Chin Med J (Engl) 2011 Mar;124(5):764-70

Transplantation Immunology Division, Department of Internal Medicine, University of Texas Southwestern Medical Center, USA.

Objective: To review the role of polymorphism of major histocompatibility complex class I-related chain A (MICA) gene and antibodies against MICA antigens in transplant immunology.

Data Sources: The data used in this review were mainly from our own results and from the relevant English language literatures published from 1999 to 2010. Some data presented in this review are in press.

Study Selection: Articles regarding MICA gene discovery and pioneering finding of antibodies against MICA antigen and allograft rejection were selected. This review chronicles the development of our understanding of the role that MICA antigens and antibodies may play in organ transplantation.

Results: Polymorphic glycoprotein MICA antigens were detected on freshly isolated human umbilical cord endothelial cells, but not on peripheral lymphocytes. Antibodies were found and typing of recipients and donors by sequencing the MICA alleles has established that de novo antibodies produced in kidney transplant recipients are directed at mismatched MICA epitopes and are associated with acute rejection and chronic transplant failure. The specificity of antibodies against the epitopes of MICA antigens were well characterized by donor MICA typing, single antigen array testing with antibody absorption and elution. Acute graft-versus-host disease was observed in stem-cell recipients who were mismatched for MICA.

Conclusions: Immunization against mismatched MICA epitopes encountered in donor organs after transplantation may result in antibodies against MICA alleles. Testing for MICA donor-specific antibodies (DSA) which are associated with early failure of kidney transplants may be helpful for identifying some of the targets of antibodies against antigens other than the human leukocyte antigen (HLA) and for improving transplantation outcome.
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March 2011

Discrepant effects of Chlamydia trachomatis infection on MICA expression of HeLa and U373 cells.

Infect Genet Evol 2010 Aug 15;10(6):740-5. Epub 2010 May 15.

Department of Immunology, College of Basic Medical Sciences, Central South University, Changsha 410008, China.

Natural killer (NK) cells are an important component of the host immune defense against Chlamydia trachomatis (CT). In this study we investigated the effects of CT on the expression of two forms of MHC class I-related chain A (MICA). One form, a truncated variant that has a partial transmembrane region and no cytoplasmic tail, was expressed in HeLa cells. The other, a full-length variant, was expressed in astrocytoma U373 cells. CT infection had little effect on the expression of the truncated form, which was constitutively expressed in HeLa cells, but expression of the full-length MICA was down-regulated in CT-infected U373 cells. Down-regulation of MICA after CT infection protected U373 cells from NK cell lysis, whereas HeLa cells expressing the truncated form were killed. This study shows that the constitutive expression of the truncated from of MICA prevents CT from evading immune recognition by NK cells.
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http://dx.doi.org/10.1016/j.meegid.2010.05.003DOI Listing
August 2010

Donor-recipient mismatches in MHC class I chain-related gene A in unrelated donor transplantation lead to increased incidence of acute graft-versus-host disease.

Blood 2009 Oct 4;114(14):2884-7. Epub 2009 Aug 4.

Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

The polymorphic products of major histocompatibility complex class I-related chain A (MICA) genes are important in solid organ transplantation rejection. MICA expression is limited to gut epithelium and may play a role in triggering acute graft-versus-host disease (aGVHD). A total of 236 recipients of unrelated donor transplantation were studied. Donor-recipient human leukocyte antigen (HLA) match was 10/10 human leukocyte antigen (HLA-A, -B, -C, -DRB1, -DQB1) in 73% and MICA mismatch in 8.4%. Because of physical vicinity of the loci, MICA mismatch was significantly associated with mismatch at HLA-B and HLA-C. A higher rate of grade II-IV aGVHD was seen in MICA-mismatched patients (80% vs 40%, P = .003) irrespective of degree of HLA matching (HLA 10/10 match: 75% vs 39%, P = .02) and HLA any mismatch (83% vs 46%, P = .003). The rate of grade II-IV gastrointestinal aGVHD was also higher in MICA-mismatched patients (35% vs 17%, P = .05). We conclude that MICA may represent novel a transplantation antigen recognized by human allogeneic T cells. This study was registered at ClinicalTrials.gov (Identifier NCT00506922).
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http://dx.doi.org/10.1182/blood-2009-05-223172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4784289PMC
October 2009

The role of major histocompatibility complex class I chain-related gene A antibodies in organ transplantation.

Curr Opin Organ Transplant 2009 Aug;14(4):414-8

Transplantation Immunology Division, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390-8886, USA.

Purpose Of Review: Major histocompatibility complex class I chain-related gene A (MICA) antigens are expressed on the endothelium, they are polymorphic and have been shown to be recognized by antibodies produced by transplant recipients. Methods for detection of these antibodies have become available. In the 15th International Histocompatibility Workshop, a study for MICA antibody testing and of MICA genotyping was organized.

Recent Findings: Antibodies against MICA antigens have been determined either using cells transfected with MICA alleles or recombinant MICA antigens. MICA epitopes were characterized by empirical study of human sera and by correlation with MICA polymorphic amino acids. Sera were absorbed with cells transfected with MICA alleles and site-directed mutagenesis was employed to analyze complex sera. A number of clinical studies have shown associations of antibodies against MICA with decreased survival of kidney transplants and in one investigation with acute rejection in recipients of heart allografts.

Summary: In addition to the HLA antigens, which elicit a strong immune response against allografted organs, the MICA antigens may be recognized as foreign and induce the production of MICA-specific antibodies. Antibodies against MICA have been associated with a decrease in the survival of organ allografts. The results suggest the MICA antigens are transplantation antigens that can induce an immune response associated with graft failure.
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http://dx.doi.org/10.1097/mot.0b013e32832d835eDOI Listing
August 2009

High levels of soluble Major Histocompatibility Complex class I related chain A (MICA) are associated with biliary cast syndrome after liver transplantation.

Transpl Immunol 2009 Sep 17;21(4):210-4. Epub 2009 Jun 17.

Department of Immunology, Xiang Ya School of Medicine, Central South University, Hunan, China.

Background: The biliary cast syndrome (BCS) is a frequent problem following liver transplantation. The pathogenesis of this complication is not well understood. Previous research has demonstrated that the soluble form of MICA (sMICA) is significantly higher in patients with chronic liver disease and hepatocellular carcinoma (HCC) than in healthy volunteers. The aim of this study is to investigate the possible involvement of sMICA in the formation of BCS after liver transplantation.

Methods: Serum soluble MICA was retrospectively evaluated in pre- and post-transplant sera from 133 consecutive primary liver transplant patients and in sera from 88 healthy volunteers using sandwich ELISA. Normal distribution of serum sMICA was described by the data obtained from healthy population and sMICA concentration that was greater than the upper bound 95% normal range was considered as high levels of sMICA. Patient records were reviewed to identify patients who developed BCS.

Results: The results demonstrated that 37.6% of patients with end-stage liver diseases had significantly higher pre-transplant serum sMICA than in healthy population. 34.4% of recipients with post-transplant high levels of sMICA developed BCS. In contrast, 17.3% of patients with post-transplant normal levels of sMICA developed BCS. The risk of BCS development is significantly associated with the presence of post-transplant high levels of sMICA (P=0.0365). Further analysis disclosed that patients with decreased post-transplant sMICA following liver transplantation had a lower incidence rate of BCS than those with remained high levels of sMICA after transplantation (10.5% vs. 38.7%, P=0.0302). Furthermore, log-rank test showed that BCS occurrence was significantly associated with dynamic changes of sMICA among different groups (P=0.0188).

Conclusions: Biliary cast syndrome is more likely to develop in recipients who have post-transplant high levels of sMICA. The data suggested that sMICA might have some immunologic effect on BCS development following liver transplant. Monitoring of serum sMICA could have a prognostic value in assessment of patients with liver transplantation.
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http://dx.doi.org/10.1016/j.trim.2009.06.003DOI Listing
September 2009

Polymorphisms of MICA recognized by human alloantibodies.

Immunogenetics 2009 Feb 10;61(2):91-100. Epub 2008 Dec 10.

Department of Internal Medicine, Division of Transplant Immunology, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8886, USA.

MICA antigens are polymorphic glycoproteins expressed on the surface of human endothelial cells and other cells. Antibodies against MICA have been found in transplant recipients and were found to be associated with decreased survival of kidney allografts. In the present work, we investigated the polymorphisms that are recognized by antibodies against MICA. Soluble MICA recombinant proteins representing 11 common alleles, two hybrid alleles, and two single amino acid mutated alleles were produced. Patterns of reactivity were determined with MICA bound to Luminex beads. In some studies, sera containing antibodies against MICA were absorbed by cell lines transfected with MICA*001, MICA*002, MICA*008, and MICA*009 or with untransfected cells, followed by testing of antibody reactivity against MICA proteins bound to beads. The monoclonal antibodies and sera used in this study were found to recognize up to 14 distinct MICA epitopes as demonstrated by their differential absorption/reactivity patterns. Among these, nine epitopes correlated with a single unique amino acid: one shared two signature amino acids, one shared three signature amino acids in close proximity, and three epitopes involved multiple amino acids in a nonlinear sequence. Two groups of public epitopes (MICA-G1 and MICA-G2) were characterized. MICA shared epitopes were determined by reactivity loss in single MICA antigen bead assays by absorption with MICA transfectants. Since these epitopes may be targets for antibody binding and possibly antibody-mediated allograft rejection, epitope identification may help understand the development of MICA antibodies and to identify suitable donors for sensitized transplant recipients.
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http://dx.doi.org/10.1007/s00251-008-0344-9DOI Listing
February 2009
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