Browsing by Author "Wang, Yan"

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    Activin B Promotes Hepatic Fibrogenesis
    (2019-08) Wang, Yan; Dai, Guoli; Berbari, Nicolas; Yaden, Benjamin; Liangpunsakul, Suthat; Skalnik, David G.
    Liver fibrosis is a common consequence of various chronic liver diseases. Although transforming growth factor β 1 (TGFβ1) expression is known to be associated with liver fibrosis, the reduced clinical efficacy of TGFβ1 inhibition or the inefficiency to completely prevent liver fibrosis in mice with liver-specific knockout of TGF receptor II suggests that other factors can mediate liver fibrogenesis. As a TGFβ superfamily ligand, activin A signaling modulates liver injury by prohibiting hepatocyte proliferation, mediating hepatocyte apoptosis, promoting Kupffer cell activation, and inducing hepatic stellate cell (HSC) activation in vitro. However, the mechanism of action and in vivo functional significance of activin A in liver fibrosis models remain uncertain. Moreover, whether activin B, another ligand structurally related to activin A, is involved in liver fibrogenesis is not yet known. This study aimed to investigate the role of activin A and B in liver fibrosis initiation and progression. The levels of hepatic and circulating activin B and A were analyzed in patients with various chronic liver diseases, including end-stage liver diseases (ESLD), non-alcoholic steatohepatitis (NASH), and alcoholic liver disease (ALD). In addition, their levels were measured in mouse carbon tetrachloride (CCl4), bile duct ligation (BDL), and ALD liver injury models. Mouse primary hepatocytes, RAW264.7 cells, and LX-2 cells were used as in vitro models of hepatocytes, macrophages, and HSCs, respectively. The specificity and potency of anti-activin B monoclonal antibody (mAb) and anti-activin A mAb were evaluated using Smad2/3 luciferase assay. Activin A, activin B, or their combination were immunologically inactivated by the neutralizing mAbs in mice with progressive or established liver fibrosis induced by CCl4 or with developing cholestatic liver fibrosis induced by BDL surgery. In patients with ESLD, NASH, and ALD, increases in hepatic and circulating activin B, but not activin A, were associated with liver fibrosis, irrespective of etiology. In mice with CCl4-, BDL-, or alcohol-induced liver injury, activin B was persistently elevated in the liver and circulation, whereas activin A showed only transient increases. Activin B was expressed and secreted mainly by the hepatocytes and other cells, including cholangiocytes, activated HSCs, and immune cells. Exogenous administration of activin B promoted hepatocyte injury, activated macrophages to release cytokines, and induced a pro-fibrotic expression profile and septa formation in HSCs. Co-treatment of activin A and B interdependently activated the chemokine (C-X-C motif) ligand 1 (CXCL1)/inducible nitric oxide synthase (iNOS) pathway in macrophages and additively upregulated connective tissue growth factor expression in HSCs. Activin B and A had redundant, unique, and interactive effects on the transcripts related to HSC activation. The neutralization of activin B attenuated the development of liver fibrosis and improved liver function in mice with CCl4- or BDL-induced liver fibrosis and largely reversed the already established liver fibrosis in the CCl4 mouse model. These effects were improved by the administration of additional anti-activin A antibody. Combination of both antibodies also inhibited hepatic and circulating inflammatory cytokine production in the BDL mouse model. In conclusion, activin B is a potential circulating biomarker and potent promotor of liver fibrosis. Its levels in the liver and circulation increase significantly in both acute and chronic states of liver injury. Activin B might additively or interdependently cooperate with activin A, which directly acts on multiple liver cell populations during liver injury and fibrosis, as the combination of both proteins increases pro-inflammatory and pro-fibrotic responses in vitro. In addition, the neutralization of both activin A and activin B in vivo enhances the preventive and reversible effects of liver injury and fibrosis compared to that when activin B alone is neutralized. Our data reveal a novel target of liver fibrosis and the mechanism of activin B-mediated initiation of this process by damaging hepatocytes and activating macrophages and HSCs. Our findings show that activin B promotes hepatic fibrogenesis, and that targeting of activin B has anti-inflammatory and anti-fibrotic effects, which ameliorate liver injury by preventing or regressing liver fibrosis. Antagonizing either activin B alone or in combination with activin A prevents and regresses liver fibrosis in multiple animal studies, paving way for future clinical studies.
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    Activin B promotes the initiation and progression of liver fibrosis
    (Wolters Kluwer, 2022) Wang, Yan; Hamang, Matthew; Culver, Alexander; Jiang, Huaizhou; Yanum, Jennifer; Garcia, Veronica; Lee, Joonyong; White, Emily; Kusumanchi, Praveen; Chalasani, Naga; Liangpunsakul, Suthat; Yaden, Benjamin C.; Dai, Guoli; Biology, School of Science
    The role of activin B, a transforming growth factor β (TGFβ) superfamily cytokine, in liver health and disease is largely unknown. We aimed to investigate whether activin B modulates liver fibrogenesis. Liver and serum activin B, along with its analog activin A, were analyzed in patients with liver fibrosis from different etiologies and in mouse acute and chronic liver injury models. Activin B, activin A, or both was immunologically neutralized in mice with progressive or established carbon tetrachloride (CCl4 )-induced liver fibrosis. Hepatic and circulating activin B was increased in human patients with liver fibrosis caused by several liver diseases. In mice, hepatic and circulating activin B exhibited persistent elevation following the onset of several types of liver injury, whereas activin A displayed transient increases. The results revealed a close correlation of activin B with liver injury regardless of etiology and species. Injured hepatocytes produced excessive activin B. Neutralizing activin B largely prevented, as well as improved, CCl4 -induced liver fibrosis, which was augmented by co-neutralizing activin A. Mechanistically, activin B mediated the activation of c-Jun-N-terminal kinase (JNK), the induction of inducible nitric oxide synthase (iNOS) expression, and the maintenance of poly (ADP-ribose) polymerase 1 (PARP1) expression in injured livers. Moreover, activin B directly induced a profibrotic expression profile in hepatic stellate cells (HSCs) and stimulated these cells to form a septa structure. Conclusions: We demonstrate that activin B, cooperating with activin A, mediates the activation or expression of JNK, iNOS, and PARP1 and the activation of HSCs, driving the initiation and progression of liver fibrosis.
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    Authenticating Users Through Fine-Grained Channel Information
    (IEEE, 2018-02) Liu, Hongbo; Wang, Yan; Liu, Jian; Yang, Jie; Chen, Yingying; Poor, H. Vincent; Engineering Technology, School of Engineering and Technology
    User authentication is the critical first step in detecting identity-based attacks and preventing subsequent malicious attacks. However, the increasingly dynamic mobile environments make it harder to always apply cryptographic-based methods for user authentication due to their infrastructural and key management overhead. Exploiting non-cryptographic based techniques grounded on physical layer properties to perform user authentication appears promising. In this work, the use of channel state information (CSI), which is available from off-the-shelf WiFi devices, to perform fine-grained user authentication is explored. Particularly, a user-authentication framework that can work with both stationary and mobile users is proposed. When the user is stationary, the proposed framework builds a user profile for user authentication that is resilient to the presence of a spoofer. The proposed machine learning based user-authentication techniques can distinguish between two users even when they possess similar signal fingerprints and detect the existence of a spoofer. When the user is mobile, it is proposed to detect the presence of a spoofer by examining the temporal correlation of CSI measurements. Both office building and apartment environments show that the proposed framework can filter out signal outliers and achieve higher authentication accuracy compared with existing approaches using received signal strength (RSS).
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    Case fatality risk of the first pandemic wave of novel coronavirus disease 2019 (COVID-19) in China
    (Oxford University Press, 2020-05-15) Deng, Xiaowei; Yang, Juan; Wang, Wei; Wang, Xiling; Zhou, Jiaxin; Chen, Zhiyuan; Li, Jing; Chen, Yinzi; Yan, Han; Zhang, Juanjuan; Zhang, Yongli; Wang, Yan; Qiu, Qi; Gong, Hui; Wei, Xianglin; Wang, Lili; Sun, Kaiyuan; Wu, Peng; Ajelli, Marco; Cowling, Benjamin J.; Viboud, Cecile; Yu, Hongjie; Epidemiology, School of Public Health
    Objective To assess the case fatality risk (CFR) of COVID-19 in mainland China, stratified by region and clinical category, and estimate key time-to-event intervals. Methods We collected individual information and aggregated data on COVID-19 cases from publicly available official sources from December 29, 2019 to April 17, 2020. We accounted for right-censoring to estimate the CFR and explored the risk factors for mortality. We fitted Weibull, gamma, and lognormal distributions to time-to-event data using maximum-likelihood estimation. Results We analyzed 82,719 laboratory-confirmed cases reported in mainland China, including 4,632 deaths, and 77,029 discharges. The estimated CFR was 5.65% (95%CI: 5.50%-5.81%) nationally, with highest estimate in Wuhan (7.71%), and lowest in provinces outside Hubei (0.86%). The fatality risk among critical patients was 3.6 times that of all patients, and 0.8-10.3 fold higher than that of mild-to-severe patients. Older age (OR 1.14 per year; 95%CI: 1.11-1.16), and being male (OR 1.83; 95%CI: 1.10-3.04) were risk factors for mortality. The time from symptom onset to first healthcare consultation, time from symptom onset to laboratory confirmation, and time from symptom onset to hospitalization were consistently longer for deceased patients than for those who recovered. Conclusions Our CFR estimates based on laboratory-confirmed cases ascertained in mainland China suggest that COVID-19 is more severe than the 2009 H1N1 influenza pandemic in hospitalized patients, particularly in Wuhan. Our study provides a comprehensive picture of the severity of the first wave of the pandemic in China. Our estimates can help inform models and the global response to COVID-19.
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    Clinical Predictors of Functional Cure in Children 1–6 Years-old with Chronic Hepatitis B
    (Xia & He, 2022) Pan, Jing; Wang, Haiyan; Yao, Tiantian; Liao, Xuejiao; Cheng, Hao; Liangpunsakul, Suthat; Wang, Yan; Zhang, Min; Zhang, Zheng; Medicine, School of Medicine
    Background and aims: Hepatitis B surface antigen (HBsAg) clearance is significantly more common in children with chronic hepatitis B (CHB) than in adults; however, the possible influencing factors related to HBsAg loss have yet to be found. This study aimed to explore the efficacy of long-term interferon (IFN)α therapy in treating children with CHB and analyzed the factors influencing functional cure after treatment. Methods: A total of 236 children aged 1-6 years and diagnosed with CHB via liver biopsy were included in the study, all receiving IFNα treatment (IFNα-2b monotherapy, IFNα-2b followed by lamivudine [LAM] or IFNα-2b combined with LAM) and followed up for 144 weeks. A comprehensive analysis was conducted on clinical data, including biochemical items, serum markers of hepatitis B virus (HBV) and immunological indexes, and logistic regression analysis was used to screen the influencing factors related to HBsAg loss. Results: The cumulative loss rates of HBsAg were 79.5%, 62.1% and 42.1% at 144 weeks after the start of treatment in the 1-3 years-old group, 3-5 years-old group and 5-7 years-old group, respectively (p<0.05). IFNα-2b combined with LAM treatment displayed the highest HBsAg loss rates compared with monotherapy and sequential treatment (p=0.011). Younger baseline age and lower HBsAg levels were independent factors for the prediction of HBsAg loss (p<0.05). The baseline PreS1 and hepatitis B core antibody levels in the HBsAg loss group were lower than those in the HBsAg non-loss group. In addition, the PreS1 level was positively corelated with the level of HBsAg, HBV DNA and liver inflammation. Conclusions: Long-term treatment with IFNα was effective in achieving HBsAg loss in CHB children aged 1-6 years-old. Age less than 3 years-old and lower HBsAg levels are independent predictors of functional cure in children with CHB.
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    Determining Driver Phone Use by Exploiting Smartphone Integrated Sensors
    (IEEE, 2016-08) Wang, Yan; Chen, Yingying (Jennifer); Yang, Jie; Gruteser, Marco; Martin, Richard P.; Liu, Hongbo; Liu, Luyang; Karatas, Cagdas; Department of Engineering Technology, School of Engineering and Technology
    This paper utilizes smartphone sensing of vehicle dynamics to determine driver phone use, which can facilitate many traffic safety applications. Our system uses embedded sensors in smartphones, i.e., accelerometers and gyroscopes, to capture differences in centripetal acceleration due to vehicle dynamics. These differences combined with angular speed can determine whether the phone is on the left or right side of the vehicle. Our low infrastructure approach is flexible with different turn sizes and driving speeds. Extensive experiments conducted with two vehicles in two different cities demonstrate that our system is robust to real driving environments. Despite noisy sensor readings from smartphones, our approach can achieve a classification accuracy of over 90 percent with a false positive rate of a few percent. We also find that by combining sensing results in a few turns, we can achieve better accuracy (e.g., 95 percent) with a lower false positive rate. In addition, we seek to exploit the electromagnetic field measurement inside a vehicle to complement vehicle dynamics for driver phone sensing under the scenarios when little vehicle dynamics is present, for example, driving straight on highways or standing at roadsides.
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    Dissection of transcriptome dysregulation and immune characterization in women with germline BRCA1 mutation at single-cell resolution
    (Springer, 2022-09-09) Yu, Xuexin; Lin, Wanrun; Spirtos, Alexandra; Wang, Yan; Chen, Hao; Ye, Jianfeng; Parker, Jessica; Liu, Ci Ci; Wang, Yiying; Quinn, Gabriella; Zhou, Feng; Chambers, Setsuko K.; Lewis, Cheryl; Lea, Jayanthi; Li, Bo; Zheng, Wenxin; Obstetrics and Gynecology, School of Medicine
    Background: High-grade serous carcinoma (HGSC) is the most frequent and lethal type of ovarian cancer. It has been proposed that tubal secretory cells are the origin of ovarian HGSC in women with familial BRCA1/2 mutations. However, the molecular changes underlying malignant transformation remain unknown. Method: We performed single-cell RNA and T cell receptor sequencing of tubal fimbriated ends from 3 BRCA1 germline mutation carriers (BRCA1 carriers) and 3 normal controls with no high-risk history (non-BRCA1 carriers). Results: Exploring the transcriptomes of 19,008 cells, predominantly from BRCA1+ samples, we identified 5 major cell populations in the fallopian tubal mucosae. The secretory cells of BRCA1+ samples had differentially expressed genes involved in tumor growth and regulation, chemokine signaling, and antigen presentation compared to the wild-type BRCA1 controls. There are several novel findings in this study. First, a subset of the fallopian tubal secretory cells from one BRCA1 carrier exhibited an epithelial-to-mesenchymal transition (EMT) phenotype, which was also present in the mucosal fibroblasts. Second, we identified a previously unreported phenotypic split of the EMT secretory cells with distinct evolutionary endpoints. Third, we observed increased clonal expansion among the CD8+ T cell population from BRCA1+ carriers. Among those clonally expanded CD8+ T cells, PD-1 was significantly increased in tubal mucosae of BRCA1+ patients compared with that of normal controls, indicating that T cell exhaustion may occur before the development of any premalignant or malignant lesions. Conclusion: These results indicate that EMT and immune evasion in normal-looking tubal mucosae may represent early events leading to the development of HGSC in women with BRCA1 germline mutation. Our findings provide a probable molecular mechanism explaining why some, but not all, women with BRCA1 germline mutation present with early development and rapid dissemination of HGSC.
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    Editorial: Ischemic stroke as systemic disorder involving both nervous and immune systems
    (Frontiers Media, 2023-05-10) Liu, Qingkun; Wang, Yan; Yen, Jui-Hung Jimmy; Microbiology and Immunology, School of Medicine
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    Environment-independent In-baggage Object Identification Using WiFi Signals
    (IEEE Xplore, 2021-10) Shi, Cong; Zhao, Tianming; Xie, Yucheng; Zhang, Tianfang; Wang, Yan; Guo, Xiaonan; Chen, Yingying; Engineering Technology, School of Engineering and Technology
    Low-cost in-baggage object identification is highly demanded in enhancing public safety and smart manufacturing. Existing approaches usually require specialized equipment and heavy deployment overhead, making them hard to scale for wide deployment. The recent WiFi-based approach is unsuitable for practical deployment as it did not address dynamic environmental impacts. In this work, we propose an environment-independent in-baggage object identification system by leveraging low-cost WiFi. We exploit the channel state information (CSI) to capture material and shape characteristics to facilitate fine-grained inbaggage object identification. A major challenge of building such a system is that CSI measurements are sensitive to real-world dynamics, such as different types of baggage, time-varying ambient noises and interferences, and different deployment environments. To tackle these problems, we develop WiFi features based on polarized directional antennas that can capture objects’ material and shape characteristics. A convolutional neural network-based model is developed to constructively integrate the WiFi features and perform accurate in-baggage object identification. We also develop a material-based domain adaptation using adversarial learning to facilitate fast deployments in different environments. We conduct extensive experiments involving 14 representation objects, 4 types of bags in 3 different room environments. The results show that our system can achieve over 97% in the same environment, and our domain adaptation method can improve the object identification accuracy by 42% when the system is deployed in a new environment with little training.
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    The functional epigenetic landscape of aberrant gene expression in molecular subgroups of newly diagnosed multiple myeloma
    (BMC, 2020-08-06) Choudhury, Samrat Roy; Ashby, Cody; Tytarenko, Ruslana; Bauer, Michael; Wang, Yan; Deshpande, Shayu; Den, Judith; Schinke, Carolina; Zangari, Maurizio; Thanendrarajan, Sharmilan; Davies, Faith E.; van Rhee, Frits; Morgan, Gareth J.; Walker, Brian A.; Medicine, School of Medicine
    Background Multiple Myeloma (MM) is a hematological malignancy with genomic heterogeneity and poor survival outcome. Apart from the central role of genetic lesions, epigenetic anomalies have been identified as drivers in the development of the disease. Methods Alterations in the DNA methylome were mapped in 52 newly diagnosed MM (NDMM) patients of six molecular subgroups and matched with loci-specific chromatin marks to define their impact on gene expression. Differential DNA methylation analysis was performed using DMAP with a ≥10% increase (hypermethylation) or decrease (hypomethylation) in NDMM subgroups, compared to control samples, considered significant for all the subsequent analyses with p<0.05 after adjusting for a false discovery rate. Results We identified differentially methylated regions (DMRs) within the etiological cytogenetic subgroups of myeloma, compared to control plasma cells. Using gene expression data we identified genes that are dysregulated and correlate with DNA methylation levels, indicating a role for DNA methylation in their transcriptional control. We demonstrated that 70% of DMRs in the MM epigenome were hypomethylated and overlapped with repressive H3K27me3. In contrast, differentially expressed genes containing hypermethylated DMRs within the gene body or hypomethylated DMRs at the promoters overlapped with H3K4me1, H3K4me3, or H3K36me3 marks. Additionally, enrichment of BRD4 or MED1 at the H3K27ac enriched DMRs functioned as super-enhancers (SE), controlling the overexpression of genes or gene-cassettes. Conclusions Therefore, this study presents the underlying epigenetic regulatory networks of gene expression dysregulation in NDMM patients and identifies potential targets for future therapies.