There is extravasation of erythrocytes and leucocytes. As the erythrocytes break down, haemoglobin and iron are released, which when minimal can be phagocytized by the synovial macrophage-like cells and sequestered. Within 1 week, blood in the joint, if not excessive, is resorbed by these synovial lining cells and subsynovial macrophages, resulting in full haemorrhage resolution [44]. If recurrent, or a massive episode of bleeding occurs, these cells are overwhelmed, and components of blood, such as iron, remain in the joint space and bathe cartilage surfaces. The role of haemoglobin and iron, specifically, has not

been clearly elucidated [45], although the possibility of aberrant gene expression has been suggested [46,47] and formation INK 128 chemical structure of reactive oxygen intermediates may play a role [40]. There is hypertrophy and hyperplasia of synovial selleck chemicals cells due to severe or repeated bleeding episodes [48]. Like a growing tumour, synovial cells require oxygen and nutrients to survive, which are initially provided by diffusion. However, once the membrane grows beyond a few cell layers in thickness, hypoxia results, invoking an angiogenic stimulus, which when combined with proangiogenic inflammatory mediators, leads to neovascularization of the membrane.

This neovascularization facilitates expansion of the synovial membrane and results in frond-like projections of the membrane along the articular surfaces, which may lead to impingement and mechanical bleeding due to vascular disruption. Direct effects of blood on cartilage are also likely as described click here above. Once the process begins, the eventual outcome is evolution into a scar-like, fibrotic arthritis now known as haemophilic arthropathy. The pathobiology of this process remains to be established [49,50]. Although many tools have been developed to assess outcomes in haemophilia patients, the most critical outcome to assess is bleeding frequency. In the absence of bleeding and specifically haemarthrosis,

joint disease is unlikely, although subclinical bleeding has been proposed to explain the arthropathy that develops in the absence of recognized bleeding [51]. More sensitive tools are needed to detect the earliest signs of bleeding. Recently, considerable attention and resources have been devoted to the evaluation of MRI to detect the earliest signs of joint disease [52–57]. In the future, more sensitive imaging modalities may become available for clinical use, such as blood-oxygen-level-dependent functional MRI, ultrasmall superparamagnetic iron-oxide contrast-enhanced MRI, T1 and T2 mapping MRI, ultrasound biomicroscopy, microbubble contrast-enhanced ultrasonography and positron emission tomography [58]. Another potential modality to monitor subclinical bleeding and the earliest signs of joint disease is the use of biomarkers [59].

There is extravasation of erythrocytes and leucocytes. As the erythrocytes break down, haemoglobin and iron are released, which when minimal can be phagocytized by the synovial macrophage-like cells and sequestered. Within 1 week, blood in the joint, if not excessive, is resorbed by these synovial lining cells and subsynovial macrophages, resulting in full haemorrhage resolution [44]. If recurrent, or a massive episode of bleeding occurs, these cells are overwhelmed, and components of blood, such as iron, remain in the joint space and bathe cartilage surfaces. The role of haemoglobin and iron, specifically, has not

been clearly elucidated [45], although the possibility of aberrant gene expression has been suggested [46,47] and formation click here of reactive oxygen intermediates may play a role [40]. There is hypertrophy and hyperplasia of synovial Volasertib solubility dmso cells due to severe or repeated bleeding episodes [48]. Like a growing tumour, synovial cells require oxygen and nutrients to survive, which are initially provided by diffusion. However, once the membrane grows beyond a few cell layers in thickness, hypoxia results, invoking an angiogenic stimulus, which when combined with proangiogenic inflammatory mediators, leads to neovascularization of the membrane.

This neovascularization facilitates expansion of the synovial membrane and results in frond-like projections of the membrane along the articular surfaces, which may lead to impingement and mechanical bleeding due to vascular disruption. Direct effects of blood on cartilage are also likely as described find more above. Once the process begins, the eventual outcome is evolution into a scar-like, fibrotic arthritis now known as haemophilic arthropathy. The pathobiology of this process remains to be established [49,50]. Although many tools have been developed to assess outcomes in haemophilia patients, the most critical outcome to assess is bleeding frequency. In the absence of bleeding and specifically haemarthrosis,

joint disease is unlikely, although subclinical bleeding has been proposed to explain the arthropathy that develops in the absence of recognized bleeding [51]. More sensitive tools are needed to detect the earliest signs of bleeding. Recently, considerable attention and resources have been devoted to the evaluation of MRI to detect the earliest signs of joint disease [52–57]. In the future, more sensitive imaging modalities may become available for clinical use, such as blood-oxygen-level-dependent functional MRI, ultrasmall superparamagnetic iron-oxide contrast-enhanced MRI, T1 and T2 mapping MRI, ultrasound biomicroscopy, microbubble contrast-enhanced ultrasonography and positron emission tomography [58]. Another potential modality to monitor subclinical bleeding and the earliest signs of joint disease is the use of biomarkers [59].

This approval was based on experience of this treatment in consecutive young patients with severe, potentially life-threatening hyperammonemia with striking improvement Palbociclib cost of outcomes.5 Hence, Na PBA became the standard of care for maintenance therapy

of UCDs in the absence of rigorous randomized, controlled clinical trials. Nevertheless, despite the improvement represented by NaPBA, it still required daily ingestion of as many as 40 large capsules every day and resulted in bad taste and gastrointestinal (GI) disturbance, even when administered by a gastrostomy tube. Hence, another modification proposed by Brusilow, glycerol phenylbutyrate (GPB), became the focus of therapeutic development. GPB is attractive because it is a liquid triglyceride prodrug of PBA, a nearly tasteless,

odorless oil devoid of sodium. GPB is hydrolyzed by human CT99021 nmr pancreatic triglyceride lipase and other lipases releasing PBA that is absorbed from the intestine and converted to the active moiety, phenylacetic acid (PAA) via β oxidation (Fig. 1).6 PAA is conjugated with glutamine in the liver and the kidney by way of N acyl-coenzyme A/L-glutamine N-acyltransferase to form phenylacetylglutamine (PAGN). Like urea, PAGN incorporates two waste nitrogens and is excreted in the urine. The article by Diaz et al. in this issue of HEPATOLOGY is a remarkable illustration that it is possible to conduct randomized, controlled trials even in ultraorphan diseases.7 However, its success depended critically on academic-industry synergy represented by the Rare Disease Clinical Research Network’s Urea Cycle Consortium,8 a pharmaceutical company (Hyperion Therapeutics, selleck screening library Inc., South San Francisco,

CA), and the patient support organization, the National Urea Cycle Disorders Foundation. The study involved 91 patients from fewer than 500 known patients with UCDs in the United States, treated with Na PBA by investigators in the Urea Cycle Consortium. The 4-week, multicenter, randomized, double-blind, cross-over phase III study was designed to evaluate the noninferiority of GPB to NaPBA in 46 adults with UCDs, some 80% of whom suffered from OTC deficiency. The primary efficacy measure was daily ammonia exposure, measured by 24-hour AUC (area under the curve) at the end of each treatment period. Subjects were administered NaPBA or GPB at equimolar doses of PBA. Twenty-four-hour ammonia AUC for the two treatments were similar, with a slight trend toward lower ammonia in the GPB group. One hyperammonemic crisis occurred on NaPBA, but none on GPB. Interestingly, GI symptoms were similar in both groups, despite better tolerability of GPB. In a pooled analysis of 65 adult and pediatric patients on 12 months of open-label GPB treatment, ammonia control was normal, and in the pediatric patients, there was significant improvement of executive function, including behavioral regulation, goal setting, planning, and self-monitoring.

pylori-infected gastric biopsies

were stimulated with GR, and interleukin (IL)-12, interferon (IFN)-γ and IL-4 transcripts were evaluated by real-time PCR. IL-12 and IFN-γ were also analyzed in lamina propria mononuclear cells (LPMCs) extracted from Hp-infected gastric biopsies and cultured with GR. GR RNA transcripts were reduced Selleckchem CHIR-99021 in biopsies from Hp-infected patients. Treatment of Hp-negative gastric biopsies with Hp culture supernatant reduced GR RNA expression. GR dose-dependently inhibited RNA expression of IL-12 and IFN-γ but not IL-4 in ex vivo cultures of mucosal explants and in cultures of gastric LPMCs from Hp-positive patients. GR is downregulated in the gastric mucosa of H. pylori-infected patients. Such a defect could contribute Navitoclax research buy to sustain the ongoing Th1-cell response. “
“Helicobacter cinaedi, an enterohepatic helicobacter species (EHS), is an important human pathogen and is associated with a wide range of

diseases, especially in immunocompromised patients. It has been convincingly demonstrated that innate immune response to certain pathogenic enteric bacteria is sufficient to initiate colitis and colon carcinogenesis in recombinase-activating gene (Rag)-2-deficient mice model. To better understand the mechanisms of human IBD and its association with development of colon cancer, we investigated whether H. cinaedi could induce pathological changes noted with murine enterohepatic helicobacter infections in the Rag2−/− mouse model. Sixty 129SvEv Rag2−/− mice mouse were experimentally or sham infected orally with H. cinaedi strain CCUG 18818. Gastrointestinal pathology and immune responses in infected and control mice were analyzed at 3, 6 and 9 months postinfection (MPI). H. cinaedi colonized the cecum, colon, and stomach in infected

mice. H. cinaedi induced typhlocolitis in Rag2−/− mice by 3 MPI and intestinal lesions became more severe by 9 MPI. H. cinaedi was also associated with the elevation of proinflammatory cytokines, interferon-γ, tumor-necrosis factor-α, IL-1β, IL-10; iNOS mRNA levels were also upregulated in the cecum of infected mice. However, changes in IL-4, IL-6, Cox-2, and c-myc mRNA expressions were not detected. Our results indicated that the Rag2−/− mouse model will be useful to continue investigating the pathogenicity of H. cinaedi, and to study the this website association of host immune responses in IBD caused by EHS. “
“Objectives:  We evaluated demographic characteristics in HIV-positive patients receiving highly active antiretroviral therapy (HAART) who had upper gastrointestinal (UGI) symptoms requiring UGI endoscopy and compared the findings in patients with and without H. Pylori coinfection. Methods:  We prospectively observed all HIV-infected patients treated with antiretroviral therapy who underwent UGI endoscopy for the first time and were tested for H. pylori from January 2004 to December 2008.

[7] More placebo-controlled studies are needed to further assess the efficacy of steroids in the treatment of various headache disorders. Practically, patients should be informed that the onset of pain relief from steroids is probably slower than that of a local anesthetic,

and thus their analgesic effect may not occur within the first 20 minutes of injections. Due to potential local and systemic AEs, the cautious use of corticosteroids is warranted in all patients, and particularly in those with diabetes or glaucoma.[22] Corticosteroids should be avoided when performing PNBs in the trigeminal branches, due to potential local AEs, including cutaneous atrophy.[10] The said recommendations represent the current recommendations among the AHS-IPS members on this topic. It should be noted that there is a paucity of evidence from controlled studies for the use of PNBs learn more in the treatment of Doxorubicin cell line primary and secondary headache disorders, with the exception of GON blockade for CH. Further research on this topic is strongly encouraged, and may result in revision of the said recommendations, aiming

at further improving the outcome and safety of this treatment modality for headache. “
“Objectives.— (1) To establish whether pre-treatment headache intensity in migraine or episodic tension-type headache (ETTH) predicts success or failure of treatment with aspirin; and (2) to reflect, accordingly, on the place of aspirin in the management of these disorders. Background.— Stepped care in migraine management

uses symptomatic treatments as first-line, reserving triptans for those in whom this proves ineffective. Stratified care chooses between symptomatic therapy and triptans as first-line on an individual basis according to perceived illness severity. We questioned the 2 assumptions underpinning stratified care in migraine that greater illness severity: (1) reflects greater need; and (2) is a risk factor for failure of symptomatic treatment but not of triptans. Methods.— With regard to the first assumption, we developed a rhetorical argument that need for treatment is underpinned by expectation of benefit, not by illness severity. To address the second, we reviewed individual patient data from see more 6 clinical trials of aspirin 1000 mg in migraine (N = 2079; 1165 moderate headache, 914 severe) and one of aspirin 500 and 1000 mg in ETTH (N = 325; 180 moderate, 145 severe), relating outcome to pre-treatment headache intensity. Results.— In migraine, for headache relief at 2 hours, a small (4.7%) and non-significant risk difference (RD) in therapeutic gain favored moderate pain; for pain freedom at 2 hours, therapeutic gains were almost identical (RD: −0.2%). In ETTH, for headache relief at 2 hours, RDs for both aspirin 500 mg (−4.2%) and aspirin 1000 mg (−9.7%) favored severe pain, although neither significantly; for pain freedom at 2 hours, RDs (−14.2 and −3.6) again favored severe pain. Conclusion.

Similarly, BM-MSCs transplantation was performed after 4-week treatment, and mice were sacrificed after an additional 4 weeks of TAA challenge. Other materials and methods, including cells, animals, reagents, isolation of BM-MSCs, histologic analysis of liver tissues, liver functional assay, colony-forming unit-fibroblast (CFU-f) assay, cell-growth assay, flow cytometry,

western blotting analysis, quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR), lentivirus production, migration, and statistical analysis, are described in the Supporting Materials. We first characterized the purity of primary isolated BM-MSCs from mice by checking their surface marker expressions and found they were highly Navitoclax supplier positive for CD44 (99.0%)

and CD29 (98.5%) and moderately positive for CD117 (29.4%) and CD106 (32.5%), but only had little expression of CD34 (0.59%) and CD45 (1.28%) (as shown in Supporting Fig. 1). These results were consistent with previous reports.15 We also compared surface marker expressions between WT BM-MSCs and ARKO BM-MSCs to see whether knockout (KO) of AR changes BM-MSCs subtypes. The results showed no significant difference between WT and ARKO BM-MSCs (Supporting Fig. 2). We then compared ARKO BM-MSCs versus WT BM-MSCs for their transplantation therapeutic efficacy in CCl4-induced liver cirrhotic mice. Quizartinib molecular weight Because BM-MSCs express Cre recombinase (Cre) and GFP, we therefore used these two markers to monitor transplantation efficacy. First, we checked whether BM-MSCs were able to migrate to the liver and found both Cre expressions and GFP signals were detected in BM-MSCs-transplanted mouse liver tissues, but not in liver tissues from healthy control or untransplanted CCl4-treated mice (Supporting Fig. 3), indicating that transplanted BM-MSCs indeed migrated to the cirrhotic liver. Histological analysis revealed that WT BM-MSCs-transplanted livers showed see more lower levels

of collagen (shown by Picro Sirus Red staining; Fig. 1A-a), fibronectin (Fig. 1A-b), and alpha smooth muscle actin (α-SMA; Fig. 1A-c), compared to untransplanted mice. Importantly, we found that ARKO BM-MSCs-transplanted liver showed even much lower fibrotic marker expressions than WT BM-MSC-transplanted liver (Fig. 1A-a-c), suggesting that WT BM-MSCs transplantation improved liver cirrhosis and that ARKO BM-MSCs further enhanced this transplantation therapeutic efficiency. Liver functional assays, performed by measuring aspartate aminotransferase (AST), alanine aminotransferase (ALT), and albumin (Fig. 1B-d-f), all showed consistent results in that BM-MSCs-transplanted mice had improvement in liver cirrhosis and that KO of AR in BM-MSCs increased transplantation therapeutic efficacy. We further confirmed these findings in the second liver cirrhosis mouse model in TAA-induced liver cirrhosis mice with consistent results (Fig.

This study was terminated early due to the drug’s remarkable success in treating a genetically defined subset of patients with breast cancer.22-24 We need a global collaborative program that addresses key pharmacogenomics and applies current innovations if we are going to lead a change in course for HCC, and lead the field of bundled care in hepatology, for one of the most common and lethal cancers worldwide. The Hepatocellular Cancer Global Consortium (HCGC) currently

at 55 Investigators, was established see more informally in 2003 and recently more formally. The HCGC is one group that is able to address specific goals: prevention, detection, and treatment AZD3965 leading to elimination of HCC.25 Clearly clinicians, scientists, and collaborative research in hepatology needs to bring new insights from innovative fields of science to ours, and apply these to the large patient population

of 2,993 HCCs in the United States. All of these resources are important elements to this process. This HCGC program proposes five potentially paradigm shifting translational projects, that include the first HCC genome-wide study in a U.S.-based population of 2,993 HCC cases, new and potentially effective therapeutics, taking advantage of a large patient population and meeting the challenge of the alarmingly rising incidence of hepatocellular selleck cancer in the United States. Although the risk factors are well

defined, the molecular mechanisms of hepatocarcinogenesis are unclear. It is known that up to 40% of HCC are clonal in origin and potentially arise from stem-like tumor initiating cells (STICs). These concepts have drawn attention to pathways that control stem-cell proliferation. Among these, genetics have revealed modulation of the transforming growth factor-β (TGF-β) pathway as a key functional pathway to STIC and HCC suppression. Moreover, E3 ligases and poly(ADP-ribose)polymerases (PARPs), are dramatically over-expressed in HCC with inactivation of TGF-β signaling, suggesting these as attractive targets for new therapeutics.26 These findings have led HCGC to deploy small-molecule compounds targeting the intracellular and nuclear oncogenic pathways that are specifically and highly activated only when the TGF-β pathway is inactivated. Such therapeutics are aimed at E3 ligases, PARP inhibition and histone deacetylase (HDAC) inhibition, that are now in Phase I trials in the United States. The combined programs take advantage of international collaborations in induced pluripotent stem cells (iPS), STIC suppression, promising to yield future replacement strategies.

Chronic HBV infection develops in 90 %of newborns, 29-40 %of children and 5-10 %of adults who were infected. Several studies have reported that the BCP/ PC mutants may be associated with progression of fulminant hepatic failure. However, virologic

and clinical features of children patients with CHB and LC have not been well documented. This study is to investigate virologic and clinical characters of basal core promoter (BCP)and precore (PC) region mutations in children with chronic hepatitis B and hepatitis B related liver cirrosis. Methods: A total of 307 patients with a CHB selleck screening library infection, including 88 with hepatitis B related liver cirrhosis and 219 with chronic hepatitis B were enrolled. The HBV genotypes and the presence of mutations in the BCP/PC regions were determined by direct sequencing. Biochemical and serological parameters as well as HBV DNA level were routinely performed. Viral DNA was extracted and subjected to a nested

PF01367338 PCR. Genotypes/subgenotypes were determined by derect DNA sequencing followed by molecular evolutionary analysis of the viral sequences. Mutations at 11 interested sites of the BCP/PC region were compared among the two groups of patients. Results: 46/307 (14.98%) were infected with genotype B and 261/307 (85.02%) with genotype C. LC and CHB patients both had a significantly higher ratio of genotype C to B (81.9%-18.1 %vs. 70.1%-29.9 %).The prevalence of BCP/PC wild-type virus was 54.3 %in CHB patients in contrast to 4.8 %in LC patients. In genotype C patients, the C1653T T1753C, A1762T, G1764A, G1896A mutations were significantly higher prevalent in LC patients.

Genotype B virus had higher 1752 mutation frequency. Genotype C virus had higher prevalence of T1753C, T1758C, A1762T, G1764A, G1896A mutation frequency compared to genotype find more B virus. CHB patients with BCP/PC mutant virus had higher viral load, whereas LC patients with BCP/PC mutant virus had higher viral load and elevated alanine aminotransferase in comparison with those with the wild-type virus. Conclusions: Children patients with genotype C virus, BCP/PC C1653T, A1762T, G1764A, G1896A mutant virus were more susceptible to develop LC, whereas high prevalence of the BCP/PC mutations was associated with CHB development. Disclosures: The following people have nothing to disclose: Yanwei Zhong, Hongfei Zhang, Shishu Zhu, Yi Dong, Zhiqiang Xu, Dawei Chen, Hui Dong, Fenglin Di, Limin Wang, Yu Gan, Fuchuan Wang.

The average percentage of infected hepatocytes in the 18 biopsies ranged from 1.3% to 53.9%. There was a significant positive correlation between the proportion of infected hepatocytes and the viral load in the serum and

the liver, but not with the HCV genotype. HCV positive cells occurred in clusters. A quantitative analysis of the spatial relationship between HCV RNA and interferon stimulated gene (ISG) mRNA expression in the subset of patients with an induced endogenous IFN system revealed a significant correlation. ISG signal intensity was lowest in uninfected cells with uninfected neighbors, intermediate in uninfected cells with at least one HCV positive neighbor, and highest in HCV positive cells. Conclusion: Over 20 years after STI571 chemical structure the cloning and identification of HCV, we have developed the first highly sensitive, specific and reproducible in situ detection systems that allows to identify HCV infected cells in liver biopsies in patients with viral loads as low as 1 0E4 IU/ml. A quantitative analysis of the number and spatial distribution of HCV infected cells and ISG expression revealed a number of fundamental question concerning HCV-host

interactions: HCV infects only hepatocytes. The percentage of infected hepatocytes varies from 1 to 54 %, and correlates with serum viral load. HCV infected cells appear in clusters, favoring a model of cell to cell transmission. Finally, the positive correlation of HCV RNA CH5424802 signals this website with ISG mRNA expression in patients with induced ISG expression reveals that HCV is the central driver of ISG induction. Disclosures: The following people have nothing to disclose: Stefan F Wieland, Zuzanna Makowska, Benedetta Campana, Diego Calabrese, Michael T. Dill, Josan Chung, Francis V. Chisari, Markus H. Heim Background: Combination therapy using peg-interferon (IFNa), ribavirin (RBV) and protease

inhibitor has improved the sustained antiviral response of chronic hepatitis C virus (HCV)1a infection. However, the treatment response has not improved significantly among patients who are prior non-responders to IFN-a and RBV and the mechanism of HCV resistance is not well understood. Aim: A persistent HCV replication cell culture model was developed to examine the impact of high-level viral replication on IFN-α and RBV treatment induced viral clearance. Methods: A persistent HCV infected cell culture model was established by using pJFH-delta V3-Rluc clone. HCV replication was confirmed by measuring the core and NS5A-Rluc protein expression by Western blotting and Renilla luciferase activity. Endoplasmic reticulum (ER) stress response due to HCV infection was measured by measuring ATF6 Firefly luciferase activity and autophagy induction was confirmed by measuring LC3II, p62 and Beclin 1 protein levels by Western blotting and immunocytochemical staining.

Methods: Collect

33 cases of Kazak esophageal squamous cell carcinoma and 38 cases of local normal esophageal tissue, and 32 cases of Han nationality esophageal squamous cell carcinoma and 34 cases of local normal esophageal tissue, useing MassARRAY methylation DNA quantitative analysis technology to detect the methylation status of smad4 gene promoter. Results: ① The average methylation rate of smad4 gene promoter CpG units were 3.44% in Han nationality PD0325901 ic50 esophageal cancer and 3.18% in control groups, the average methylation rate of smad4 gene promoter CpG units were 3.41% in Kazak esophageal cancer and 2.51% in control groups, the difference was not statistically significant (P > 0.05). ② The average methylation rate of smad4 gene in Han nationality esophageal CpG units 15 (4.75%) is significantly PF-02341066 manufacturer higher than the control group (3.62%); The average methylation rate of smad4 gene in Kazak esophageal CpG units 1, CpG units 16–19, units 27–28, units 31–33 (1.66%, 4.34%, 4.81%, 6.81%) were

signific- antly higher than the control group (0.72%, 2.24%, 3.06%, 5.51%), the average methylation rate of CpG units 6 in Kazak esophageal cancer (1.84%) is significantly higher than Han nationality cancer (0.44%); The average methylation rate of CpG units 14, units 16 between Kazak (6.51%, 4.34%) and Han nationality (6.87%, 4.03%) normal tissue were difference; the average methylation rate of CpG units 6, units 15, units 16–19, units 27–28, units 31–33 between Kazak (0.011%, 0.031%, 0.022%, 0.030%, 0.055%) and Han nationality (0.004%, 0.048%, 0.040%, 0.049%, 0.078%) normal tissue were difference; the difference was statistically significant (P < 0.05). Conclusion: ① Smad4 gene promoter hypermethylation was Participate in esophageal cancer both in Kazak esophageal cancer and Han nationality

esophageal cancer and may be used as diagnostic markers. ② Smad4 gene promoter hypermethylation in CpG Unit 15 may connected with the Kazakh esophageal cancer. Hypermethylation in CpG units selleck chemicals 1, units 16–19, units 27–28, units 31–33 may be the early events and connected with the Kazakh esophageal cancer. Smad4 gene promoter hypermethylation in CpG Unit 6, Unit 16–19 may the reason that High incidence of Kazakh esophageal cancer than Han nationality esophageal cancer. Key Word(s): 1. Han nationality; 2. Kazak; 3. smad4 gene; 4. esophageal cancer; Presenting Author: QINGXIANG YU Additional Authors: BANGMAO WANG Corresponding Author: BANGMAO WANG Affiliations: qingxiang.yu@qq.