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Wang B, Qiang L, Zhang G, Chen W, Sheng Y, Wu G, Deng C, Zeng S, Zhang Q. APOC3 as a potential prognostic factor for hepatitis B virus-related acute-on-chronic liver failure. Medicine (Baltimore) 2025; 104:e41503. [PMID: 39928771 PMCID: PMC11813016 DOI: 10.1097/md.0000000000041503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Revised: 12/13/2024] [Accepted: 01/23/2025] [Indexed: 02/12/2025] Open
Abstract
Acute-on-chronic liver failure (ACLF) is the major cause of mortality in patients infected with the hepatitis B virus (HBV); however, early determination of the prognosis of patients with HBV-ACLF is insensitive or limited. This study aimed to analyze differentially expressed proteins in the plasma of patients with HBV-ACLF using data-independent acquisition mass spectrometry to provide a reference for short-term prognosis. Fifty HBV-ACLF patients and 15 healthy controls were enrolled in this study. Of these, 10 patients with HBV-ACLF and 5 healthy volunteers participated in data-independent acquisition-based proteomics and the potential core proteins were screened out via bioinformatics. Apolipoprotein C3 (APOC3) was selected and quantified by enzyme linked immunosorbent assays in all patients. And the area under the curve (AUC) was calculated to evaluate the value of APOC3 in the diagnosis and prognosis of patients with HBV-ACLF. A total of 247 differentially expressed proteins were identified in the serum of patients in the HBV-ACLF and normal control groups. A total of 148 proteins were upregulated and 99 proteins were downregulated in the HBV-ACLF group compared with those in the normal group. The expression level of APOC3 was 1.65 ± 0.44 mg/mL in patients with HBV-ACLF, which was obviously lower than the normal controls (2.04 ± 0.22 mg/mL) (P < .001) (AUC was 0.766, with a sensitivity of 62%, and specificity of 93.3%). The expression level of APOC3 was 1.38 ± 0.44 mg/mL in the non-survival group, which was obviously lower than the survival group (1.83 ± 0.35 mg/mL) (P < .0001) (AUC was 0.780, with a sensitivity of 50%, and specificity of 96.7%). APOC3 is associated with short-term prognosis of patients with HBV-ACLF and can be used as a potential prognostic biomarker in patients with HBV-ACLF.
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Affiliation(s)
- Bo Wang
- Department of Infectious Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Li Qiang
- Department of Infectious Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Geng Zhang
- Department of Infectious Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Wen Chen
- Department of Infectious Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Yunjian Sheng
- Department of Infectious Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Gang Wu
- Department of Infectious Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Cunliang Deng
- Department of Infectious Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Shan Zeng
- Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Qian Zhang
- Department of Infectious Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
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Abstract
In this editorial, the roles of orosomucoid (ORM) in the diagnoses and follow-up assessments of both nonneoplastic diseases and liver tumors are discussed with respect to the publication by Zhu et al presented in the previous issue of World Journal of Gastroenterology (2020; 26(8): 840-817). ORM, or alpha-1 acid glycoprotein (AGP), is an acute-phase protein that constitutes 1% to 3% of plasma proteins in humans and is mainly synthesized in the liver. ORM exists in serum as two variants: ORM1 and ORM2. Although the variants share 89.6% sequence identity and have similar biological properties, ORM1 constitutes the main component of serum ORM. An interesting feature of ORM is that its biological effects differ according to variations in glycosylation patterns. This variable feature makes ORM an attractive target for diagnosing and monitoring many diseases, including those of the liver. Recent findings suggest that a sharp decrease in ORM level is an important marker for HBV-associated acute liver failure (ALF), and ORM1 plays an important role in liver regeneration. In viral hepatitis, increases in both ORM and its fucosylated forms and the correlation of these increases with fibrosis progression suggest that this glycoprotein can be used with other markers as a noninvasive method in the follow-up assessment of diseases. In addition, similar findings regarding the level of the asialylated form of ORM, called asialo-AGP (AsAGP), have been reported in a follow-up assessment of fibrosis in chronic liver disease. An increase in ORM in serum has also been shown to improve hepatocellular carcinoma (HCC) diagnosis performance when combined with other markers. In addition, determination of the ORM level has been useful in the diagnosis of HCC with AFP concentrations less than 500 ng/mL. For monitoring patients with AFP-negative HCC, a unique trifucosylated tetra-antennary glycan of ORM may also be used as a new potential marker. The fact that there are very few studies investigating the expression of this glycoprotein and its variants in liver tissues constitutes a potential limitation, especially in terms of revealing all the effects of ORM on carcinogenesis and tumor behavior. Current findings indicate that ORM2 expression is decreased in tumors, and this is related to the aggressive course of the disease. Parallel to this finding, in HCC cell lines, ORM2 decreases HCC cell migration and invasion, supporting reports of its tumor suppressor role. In conclusion, the levels of ORM and its different glycosylated variants are promising additional biomarkers for identifying ALF, for monitoring fibrosis in viral hepatitis, and for diagnosing early HCC. Although there is evidence that the loss of ORM2 expression in HCC is associated with poor prognosis, further studies are needed to support these findings. Additionally, investigations of ORM expression in borderline dysplastic nodules and hepatocellular adenomas, which pose diagnostic problems in the differential diagnosis of HCC, especially in biopsy samples, may shed light on whether ORM can be used in histopathological differential diagnosis.
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Affiliation(s)
- Gulsum Ozlem Elpek
- Department of Pathology, Akdeniz University Medical School, Antalya 07070, Turkey
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Zhang J, Gao J, Lin D, Xiong J, Wang J, Chen J, Lin B, Gao Z. Potential Networks Regulated by MSCs in Acute-On-Chronic Liver Failure: Exosomal miRNAs and Intracellular Target Genes. Front Genet 2021; 12:650536. [PMID: 33968135 PMCID: PMC8102832 DOI: 10.3389/fgene.2021.650536] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Accepted: 03/30/2021] [Indexed: 12/20/2022] Open
Abstract
Acute-on-chronic liver failure (ACLF) is a severe syndrome associated with high mortality. Alterations in the liver microenvironment are one of the vital causes of immune damage and liver dysfunction. Human bone marrow mesenchymal stem cells (hBMSCs) have been reported to alleviate liver injury via exosome-mediated signaling; of note, miRNAs are one of the most important cargoes in exosomes. Importantly, the miRNAs within exosomes in the hepatic microenvironment may mediate the mesenchymal stem cell (MSC)-derived regulation of liver function. This study investigated the hepatocyte exosomal miRNAs which are regulated by MSCs and the target genes which have potential in the treatment of liver failure. Briefly, ACLF was induced in mice using carbon tetrachloride and primary hepatocytes were isolated and co-cultured (or not) with MSCs under serum-free conditions. Exosomes were then collected, and the expression of exosomal miRNAs was assessed using next-generation sequencing; a comparison was performed between liver cells from healthy versus ACLF animals. Additionally, to identify the intracellular targets of exosomal miRNAs in humans, we focused on previously published data, i.e., microarray data and mass spectrometry data in liver samples from ACLF patients. The biological functions and signaling pathways associated with differentially expressed genes were predicted using gene ontology and Kyoto Encyclopedia of Genes and Genomics enrichment analyses; hub genes were also screened based on pathway analysis and the prediction of protein-protein interaction networks. Finally, we constructed the hub gene-miRNA network and performed correlation analysis and qPCR validation. Importantly, our data revealed that MSCs could regulate the miRNA content within exosomes in the hepatic microenvironment. MiR-20a-5p was down-regulated in ACLF hepatocytes and their exosomes, while the levels of chemokine C-X-C Motif Chemokine Ligand 8 (CXCL8; interleukin 8) were increased in hepatocytes. Importantly, co-culture with hBMSCs resulted in up-regulated expression of miR-20a-5p in exosomes and hepatocytes, and down-regulated expression of CXCL8 in hepatocytes. Altogether, our data suggest that the exosomal miR-20a-5p/intracellular CXCL8 axis may play an important role in the reduction of liver inflammation in ACLF in the context of MSC-based therapies and highlights CXCL8 as a potential target for alleviating liver injury.
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Affiliation(s)
- Jing Zhang
- Department of Infectious Diseases, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Juan Gao
- Department of Infectious Diseases, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Dengna Lin
- Department of Infectious Diseases, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jing Xiong
- Department of Infectious Diseases, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jialei Wang
- Department of Infectious Diseases, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Junfeng Chen
- Department of Infectious Diseases, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Bingliang Lin
- Department of Infectious Diseases, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Key Laboratory of Tropical Disease Control, Sun Yat-sen University, Ministry of Education, Guangzhou, China
| | - Zhiliang Gao
- Department of Infectious Diseases, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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Wu D, Zhang S, Xie Z, Chen E, Rao Q, Liu X, Huang K, Yang J, Xiao L, Ji F, Jiang Z, Zhao Y, Ouyang X, Zhu D, Dai X, Hou Z, Liu B, Deng B, Zhou N, Gao H, Sun Z, Li L. Plasminogen as a prognostic biomarker for HBV-related acute-on-chronic liver failure. J Clin Invest 2020; 130:2069-2080. [PMID: 32175919 PMCID: PMC7108894 DOI: 10.1172/jci130197] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Accepted: 01/14/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUNDHBV-related acute-on-chronic liver failure (HBV-ACLF) is hallmarked by high short-term mortality rates, calling for accurate prognostic biomarkers for initial risk stratification.METHODSThree tandem mass tag-labeled (TMT-labeled) quantitative proteomic studies were performed on 10 patients with HBV-related acute hepatic decompensation and on 20 patients with HBV-ACLF. Candidate biomarkers were preliminarily verified in a cross-sectional cohort (n = 144) and further confirmed in 2 prospective cohorts (n = 207 and n = 148).RESULTSPlasminogen, a potential prognostic biomarker for HBV-ACLF, was identified by TMT quantitative proteomics and preliminarily verified in the cross-sectional cohort. Further validation with a prospective cohort (n = 207) showed that plasminogen levels at admission were significantly lower (P < 0.001) in HBV-ACLF nonsurvivors than in survivors. The cumulative survival duration of patients with high plasminogen levels was significantly longer (P < 0.001) than that of patients with low plasminogen levels. During hospitalization, plasminogen levels significantly decreased (P = 0.008) in the deterioration group but significantly increased (P < 0.001) in the improvement group. Additionally, plasminogen levels gradually increased in survivors but gradually decreased in nonsurvivors. The P5 score, a prognostic panel incorporating plasminogen levels, hepatic encephalopathy occurrence, age, international normalized ratio (INR), and total bilirubin, was significantly superior to the Child-Pugh, Model for End-stage Liver Disease (MELD), Chronic Liver Failure Consortium ACLF (CLIF-C ACLF), Chinese Group on the Study of Severe Hepatitis B (COSSH), and HINT (a prognostic score based on hepatic encephalopathy occurrence, INR, neutrophil count, and thyroid-stimulating hormone) scores (all P < 0.05). The performances of the plasminogen level and P5 score were validated in a second multicenter, prospective cohort (n = 148).CONCLUSIONSPlasminogen is a promising prognostic biomarker for HBV-ACLF, and sequential plasminogen measurements could profile the clinical course of HBV-ACLF. P5 is a high-performance prognostic score for HBV-ACLF.FUNDINGThe National Key Research and Development Program (2017YFC1200204); the National Natural Science Foundation of China (81400589, 81600497); the Foundation for Innovative Research Groups of the National Natural Science Foundation of China (81121002); the Chinese High-Tech Research and Development Programs (2012AA020204); the National S&T Major Project (2012ZX10002004); and the Zhejiang Provincial Medicine and Health Science and Technology Project (2016147735).
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Affiliation(s)
- Daxian Wu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases; National Clinical Research Center for Infectious Diseases; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases; The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
- Department of Infectious Diseases, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Sainan Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases; National Clinical Research Center for Infectious Diseases; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases; The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Zhongyang Xie
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases; National Clinical Research Center for Infectious Diseases; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases; The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Ermei Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases; National Clinical Research Center for Infectious Diseases; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases; The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Qunfang Rao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases; National Clinical Research Center for Infectious Diseases; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases; The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Xiaoli Liu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases; National Clinical Research Center for Infectious Diseases; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases; The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Kaizhou Huang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases; National Clinical Research Center for Infectious Diseases; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases; The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Jing Yang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases; National Clinical Research Center for Infectious Diseases; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases; The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Lanlan Xiao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases; National Clinical Research Center for Infectious Diseases; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases; The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Feiyang Ji
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases; National Clinical Research Center for Infectious Diseases; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases; The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Zhengyi Jiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases; National Clinical Research Center for Infectious Diseases; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases; The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Yalei Zhao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases; National Clinical Research Center for Infectious Diseases; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases; The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Xiaoxi Ouyang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases; National Clinical Research Center for Infectious Diseases; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases; The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Danhua Zhu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases; National Clinical Research Center for Infectious Diseases; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases; The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Xiahong Dai
- Department of Infectious Diseases, Shulan Hospital of Hangzhou, Hangzhou, China
| | - Zhouhua Hou
- Department of Infectious Diseases, Xiangya Hospital of Central South University, Changsha, China
| | - Bingjie Liu
- Department of Infectious Diseases, First Affiliated Hospital, College of Medicine, Nanhua University, Hengyang, China
| | - Binbin Deng
- Department of Infectious Diseases, Xiangya Hospital of Central South University, Changsha, China
| | - Ning Zhou
- Department of Infectious Diseases, Second Xiangya Hospital, Central South University, Changsha, China
| | - Hainv Gao
- Department of Infectious Diseases, Shulan Hospital of Hangzhou, Hangzhou, China
| | - Zeyu Sun
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases; National Clinical Research Center for Infectious Diseases; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases; The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases; National Clinical Research Center for Infectious Diseases; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases; The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
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Ren Y, Choi E, Zhang K, Chen Y, Ye S, Deng X, Zhang K, Bao X. Detection of Nuclear Protein Profile Changes by Human Metapneumovirus M2-2 Protein Using Quantitative Differential Proteomics. Vaccines (Basel) 2017; 5:vaccines5040045. [PMID: 29207503 PMCID: PMC5748611 DOI: 10.3390/vaccines5040045] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2017] [Revised: 11/14/2017] [Accepted: 11/29/2017] [Indexed: 01/28/2023] Open
Abstract
Human metapneumovirus (hMPV) is a leading cause of lower respiratory infection in pediatric populations globally. This study examined proteomic profile changes in A549 cells infected with hMPV and two attenuated mutants with deleted PDZ domain-binding motif(s) in the M2-2 protein. These motifs are involved in the interruption of antiviral signaling, namely the interaction between the TNF receptor associated factor (TRAF) and mitochondrial antiviral-signaling (MAVS) proteins. The aim of this study was to provide insight into the overall and novel impact of M2-2 motifs on cellular responses via an unbiased comparison. Tandem mass tagging, stable isotope labeling, and high-resolution mass spectrometry were used for quantitative proteomic analysis. Using quantitative proteomics and Venn analysis, 1248 common proteins were detected in all infected samples of both technical sets. Hierarchical clustering of the differentiated proteome displayed distinct proteomic signatures that were controlled by the motif(s). Bioinformatics and experimental analysis confirmed the differentiated proteomes, revealed novel cellular biological events, and implicated key pathways controlled by hMPV M2-2 PDZ domain-binding motif(s). This provides further insight for evaluating M2-2 mutants as potent vaccine candidates.
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Affiliation(s)
- Yuping Ren
- Department of Pediatrics, University of Texas Medical Branch, Galveston, TX 77555, USA.
- Department of Plastic Surgery, TongJi Hospital, TongJi Medical College, Huazhong University of Science and Technology, Wuhan 430073, China.
| | - Eunjin Choi
- Department of Pediatrics, University of Texas Medical Branch, Galveston, TX 77555, USA.
| | - Ke Zhang
- Department of Biochemistry, Baylor University, Waco, TX 76706, USA.
| | - Yu Chen
- Department of Pediatrics, University of Texas Medical Branch, Galveston, TX 77555, USA.
- Department of Pediatrics, TongJi Hospital, TongJi Medical College, Huazhong University of Science and Technology, Wuhan 430073, China.
| | - Sha Ye
- Department of Pediatrics, University of Texas Medical Branch, Galveston, TX 77555, USA.
- Department of Gynecologic Oncology Ward V, Hunan Cancer Hospital, Xiangya School of Medicine, Central South University, Changsha 410008, China.
| | - Xiaoling Deng
- Department of Pediatrics, University of Texas Medical Branch, Galveston, TX 77555, USA.
| | - Kangling Zhang
- Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA.
| | - Xiaoyong Bao
- Department of Pediatrics, University of Texas Medical Branch, Galveston, TX 77555, USA.
- Sealy Center for Molecular Medicine, University of Texas Medical Branch, Galveston, TX 77555, USA.
- The Institute of Translational Science, University of Texas Medical Branch, Galveston, TX 77555, USA.
- The Institute for Human Infections & Immunity, University of Texas Medical Branch, Galveston, TX 77555, USA.
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