Browsing by Author "Wu, Hao"

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    A new noninvasive and patient-specific hemodynamic index for the severity of renal stenosis and outcome of interventional treatment
    (Wiley, 2022-07) Yu, Huidan; Khan, Monsurul; Wu, Hao; Du, Xiaoping; Chen, Rou; Rollins, Dave M.; Fang, Xin; Long, Jianyun; Xu, Chenke; Sawchuk, Alan P.; Surgery, School of Medicine
    Renal arterial stenosis (RAS) often causes renovascular hypertension, which may result in kidney failure and life-threatening consequences. Direct assessment of the hemodynamic severity of RAS has yet to be addressed. In this work, we present a computational concept to derive a new, noninvasive, and patient-specific index to assess the hemodynamic severity of RAS and predict the potential benefit to the patient from a stenting therapy. The hemodynamic index is derived from a functional relation between the translesional pressure indicator (TPI) and lumen volume reduction (S) through a parametric deterioration of the RAS. Our in-house computational platform, InVascular, for image-based computational hemodynamics is used to compute the TPI at given S. InVascular integrates unified computational modeling for both image processing and computational hemodynamics with graphic processing unit parallel computing technology. The TPI-S curve reveals a pair of thresholds of S indicating mild or severe RAS. The TPI at S = 0 represents the pressure improvement following a successful stenting therapy. Six patient cases with a total of 6 aortic and 12 renal arteries are studied. The computed blood pressure waveforms have good agreements with the in vivo measured ones and the systolic pressure is statistical equivalence to the in-vivo measurements with p < .001. Uncertainty quantification provides the reliability of the computed pressure through the corresponding 95% confidence interval. The severity assessments of RAS in four cases are consistent with the medical practice. The preliminary results inspire a more sophisticated investigation for real medical insights of the new index. This computational concept can be applied to other arterial stenoses such as iliac stenosis. Such a noninvasive and patient-specific hemodynamic index has the potential to aid in the clinical decision-making of interventional treatment with reduced medical cost and patient risks.
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    Bcl6 promotes follicular helper T-cell differentiation and PD-1 expression in a Blimp1-independent manner in mice
    (Wiley, 2017-07) Xie, Markus M.; Koh, Byung-Hee; Hollister, Kristin; Wu, Hao; Sun, Jie; Kaplan, Mark H.; Dent, Alexander L.; Department of Microbiology and Immunology, IU School of Medicine
    The transcription factors Bcl6 and Blimp1 have opposing roles in the development of the follicular helper T (TFH) cells: Bcl6 promotes and Blimp1 inhibits TFH-cell differentiation. Similarly, Bcl6 activates, while Blimp1 represses, expression of the TFH-cell marker PD-1. However, Bcl6 and Blimp1 repress each other's expression, complicating the interpretation of the regulatory network. Here we sought to clarify the extent to which Bcl6 and Blimp1 independently control TFH-cell differentiation by generating mice with T-cell specific deletion of both Bcl6 and Blimp1 (double conditional KO [dcKO] mice). Our data indicate that Blimp1 does not control TFH-cell differentiation independently of Bcl6. However, a population of T follicular regulatory (TFR) cells developed independently of Bcl6 in dcKO mice. We have also analyzed regulation of IL-10 and PD-1, two genes controlled by both Bcl6 and Blimp1, and observed that Bcl6 regulates both genes independently of Blimp1. We found that Bcl6 positively regulates PD-1 expression by inhibiting the ability of T-bet/Tbx21 to repress Pdcd1 transcription. Our data provide a novel mechanism for positive control of gene expression by Bcl6, and illuminate how Bcl6 and Blimp1 control TFH-cell differentiation.
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    Cell adhesion molecule CD166 drives malignant progression and osteolytic disease in multiple myeloma
    (American Association for Cancer Research, 2016-12-01) Xu, Linlin; Mohammad, Khalid S.; Wu, Hao; Crean, Colin; Poteat, Bradley; Cheng, Yinghua; Cardoso, Angelo A.; Machal, Christophe; Hanenberg, Helmut; Abonour, Rafat; Kacena, Melissa A.; Chirgwin, John; Suvannasankha, Attaya; Srour, Edward F.; Microbiology and Immunology, School of Medicine
    Multiple myeloma (MM) is incurable once osteolytic lesions have seeded at skeletal sites, but factors mediating this deadly pathogenic advance remain poorly understood. Here we report evidence of a major role for the cell adhesion molecule CD166, which we discovered to be highly expressed in MM cell lines and primary bone marrow (BM) cells from patients. CD166+ MM cells homed more efficiently than CD166− cells to the BM of engrafted immunodeficient NSG mice. CD166 silencing in MM cells enabled longer survival, a smaller tumor burden and less osteolytic lesions, as compared to mice bearing control cells. CD166 deficiency in MM cell lines or CD138+ BM cells from MM patients compromised their ability to induce bone resorption in an ex vivo organ culture system. Further, CD166 deficiency in MM cells also reduced formation of osteolytic disease in vivo after intra-tibial engraftment. Mechanistic investigation revealed that CD166 expression in MM cells inhibited osteoblastogenesis of BM-derived osteoblast progenitors by suppressing RUNX2 gene expression. Conversely, CD166 expression in MM cells promoted osteoclastogenesis by activating TRAF6-dependent signaling pathways in osteoclast progenitors. Overall, our results define CD166 as a pivotal director in MM cell homing to the BM and MM progression, rationalizing its further study as a candidate therapeutic target for MM treatment.
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    Envelope Method for Time- and Space-Dependent Reliability Prediction
    (ASCE-ASME, 2022-12) Wu, Hao; Du, Xiaoping; Mechanical and Energy Engineering, School of Engineering and Technology
    Reliability can be predicted by a limit-state function, which may vary with time and space. This work extends the envelope method for a time-dependent limit-state function to a time- and space-dependent limit-state function. The proposed method uses the envelope function of time- and space-dependent limit-state function. It at first searches for the most probable point (MPP) of the envelope function using the sequential efficient global optimization in the domain of the space and time under consideration. Then the envelope function is approximated by a quadratic function at the MPP for which analytic gradient and Hessian matrix of the envelope function are derived. Subsequently, the second-order saddlepoint approximation method is employed to estimate the probability of failure. Three examples demonstrate the effectiveness of the proposed method. The method can efficiently produce an accurate reliability prediction when the MPP is within the domain of the space and time under consideration.
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    Ethnicity-specific and overlapping alterations of brain hydroxymethylome in Alzheimer’s disease
    (Oxford University Press, 2020-01) Qin, Lixia; Xu, Qian; Li, Ziyi; Chen, Li; Li, Yujing; Yang, Nannan; Liu, Zhenhua; Guo, Jifeng; Shen, Lu; Allen, Emily G.; Chen, Chao; Ma, Chao; Wu, Hao; Zhu, Xiongwei; Jin, Peng; Tang, Beisha; Medicine, School of Medicine
    5-Methylcytosine (5mC), generated through the covalent addition of a methyl group to the fifth carbon of cytosine, is the most prevalent DNA modification in humans and functions as a critical player in the regulation of tissue and cell-specific gene expression. 5mC can be oxidized to 5-hydroxymethylcytosine (5hmC) by ten–eleven translocation (TET) enzymes, which is enriched in brain. Alzheimer’s disease (AD) is the most common neurodegenerative disorder, and several studies using the samples collected from Caucasian cohorts have found that epigenetics, particularly cytosine methylation, could play a role in the etiological process of AD. However, little research has been conducted using the samples of other ethnic groups. Here we generated genome-wide profiles of both 5mC and 5hmC in human frontal cortex tissues from late-onset Chinese AD patients and cognitively normal controls. We identified both Chinese-specific and overlapping differentially hydroxymethylated regions (DhMRs) with Caucasian cohorts. Pathway analyses revealed specific pathways enriched among Chinese-specific DhMRs, as well as the shared DhMRs with Caucasian cohorts. Furthermore, two important transcription factor-binding motifs, hypoxia-inducible factor 2α (HIF2α) and hypoxia-inducible factor 1α (HIF1α), were enriched in the DhMRs. Our analyses provide the first genome-wide profiling of DNA hydroxymethylation of the frontal cortex of AD patients from China, emphasizing an important role of 5hmC in AD pathogenesis and highlighting both ethnicity-specific and overlapping changes of brain hydroxymethylome in AD.
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    Follicular regulatory T cells repress cytokine production by follicular helper T cells and optimize IgG responses in mice
    (Wiley, 2016-05) Wu, Hao; Chen, Yuxin; Liu, Hong; Xu, Lin-Lin; Teuscher, Paula; Wang, Shixia; Lu, Shan; Dent, Alexander L.; Department of Microbiology & Immunology, IU School of Medicine
    Follicular helper T (Tfh) cells provide crucial help to germinal center B (GCB) cells for proper antibody production, and a specialized subset of regulatory T cells, follicular regulatory T (Tfr) cells, modulate this process. However, Tfr-cell function in the GC is not well understood. Here, we define Tfr cells as a CD4(+) Foxp3(+) CXCR5(hi) PD-1(hi) CD25(low) TIGIT(high) T-cell population. Furthermore, we have used a novel mouse model ("Bcl6FC") to delete the Bcl6 gene in Foxp3(+) T cells and thus specifically deplete Tfr cells. Following immunization, Bcl6FC mice develop normal Tfh- and GCB-cell populations. However, Bcl6FC mice produce altered antigen-specific antibody responses, with reduced titers of IgG and significantly increased IgA. Bcl6FC mice also developed IgG antibodies with significantly decreased avidity to antigen in an HIV-1 gp120 "prime-boost" vaccine model. In an autoimmune lupus model, we observed strongly elevated anti-DNA IgA titers in Bcl6FC mice. Additionally, Tfh cells from Bcl6FC mice consistently produce higher levels of Interferon-γ, IL-10 and IL-21. Loss of Tfr cells therefore leads to highly abnormal Tfh-cell and GCB-cell responses. Overall, our study has uncovered unique regulatory roles for Tfr cells in the GC response.
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    High-throughput functional dissection of noncoding SNPs with biased allelic enhancer activity for insulin resistance-relevant phenotypes
    (Elsevier, 2023) Duan, Yuan-Yuan; Chen, Xiao-Feng; Zhu, Ren-Jie; Jia, Ying-Ying; Huang, Xiao-Ting; Zhang, Meng; Yang, Ning; Dong, Shan-Shan; Zeng, Mengqi; Feng, Zhihui; Zhu, Dong-Li; Wu, Hao; Jiang, Feng; Shi, Wei; Hu, Wei-Xin; Ke, Xin; Chen, Hao; Liu, Yunlong; Jing, Rui-Hua; Guo, Yan; Li, Meng; Yang, Tie-Lin; Medical and Molecular Genetics, School of Medicine
    Most of the single-nucleotide polymorphisms (SNPs) associated with insulin resistance (IR)-relevant phenotypes by genome-wide association studies (GWASs) are located in noncoding regions, complicating their functional interpretation. Here, we utilized an adapted STARR-seq to evaluate the regulatory activities of 5,987 noncoding SNPs associated with IR-relevant phenotypes. We identified 876 SNPs with biased allelic enhancer activity effects (baaSNPs) across 133 loci in three IR-relevant cell lines (HepG2, preadipocyte, and A673), which showed pervasive cell specificity and significant enrichment for cell-specific open chromatin regions or enhancer-indicative markers (H3K4me1, H3K27ac). Further functional characterization suggested several transcription factors (TFs) with preferential allelic binding to baaSNPs. We also incorporated multi-omics data to prioritize 102 candidate regulatory target genes for baaSNPs and revealed prevalent long-range regulatory effects and cell-specific IR-relevant biological functional enrichment on them. Specifically, we experimentally verified the distal regulatory mechanism at IRS1 locus, in which rs952227-A reinforces IRS1 expression by long-range chromatin interaction and preferential binding to the transcription factor HOXC6 to augment the enhancer activity. Finally, based on our STARR-seq screening data, we predicted the enhancer activity of 227,343 noncoding SNPs associated with IR-relevant phenotypes (fasting insulin adjusted for BMI, HDL cholesterol, and triglycerides) from the largest available GWAS summary statistics. We further provided an open resource (http://www.bigc.online/fnSNP-IR) for better understanding genetic regulatory mechanisms of IR-relevant phenotypes.
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    An Inhibitory Role for the Transcription Factor Stat3 in Controlling IL-4 and Bcl6 Expression in Follicular Helper T cells
    (American Association of Immunologists, 2015-09) Wu, Hao; Xu, Lin-lin; Teuscher, Paulla; Liu, Hong; Kaplan, Mark H.; Dent, Alexander L.; Department of Microbiology and Immunology, IU School of Medicine
    The transcription factor Bcl6 is required for the development of the follicular helper T (TFH) cells. Cytokines that activate Stat3 promote Bcl6 expression and TFH cell differentiation. Previous studies with an acute virus infection model showed that TFH cell differentiation was decreased but not blocked in the absence of Stat3. In this study, we further analyzed the role of Stat3 in TFH cells. In Peyer’s patches (PPs), we found that compared to wild-type, Stat3-deficient TFH cells developed at a 25% lower rate, and expressed increased IFNγ and IL-4. While PP germinal center B (GCB) cells developed at normal numbers with Stat3-deficient TFH cells, IgG1 class switching was greatly increased. Following immunization with Sheep Red Blood Cells (SRBC), splenic Stat3-deficient TFH cells developed at a slower rate than in control mice and splenic GCB cells were markedly decreased. Stat3-deficient TFH cells developed poorly in a competitive bone marrow chimera environment. Under all conditions tested, Stat3-deficient TFH cells over-expressed both IL-4 and Bcl6, a pattern specific for the TFH cell population. Finally, we found in vitro that repression of IL-4 expression in CD4 T cells by Bcl6 required Stat3 function. Our data indicate that Stat3 can repress the expression of Bcl6 and IL-4 in TFH cells, and that Stat3 regulates the ability of Bcl6 to repress target genes. Overall, we conclude that Stat3 is required to fine-tune the expression of multiple key genes in TFH cells, and that the specific immune environment determines the function of Stat3 in TFH cells.
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    Inlet and Outlet Boundary Conditions and Uncertainty Quantification in Volumetric Lattice Boltzmann Method for Image-Based Computational Hemodynamics
    (MDPI, 2022-01-10) Yu, Huidan; Khan, Monsurul; Wu, Hao; Zhang, Chunze; Du, Xiaoping; Chen, Rou; Fang, Xin; Long, Jianyun; Sawchuk, Alan P.; Surgery, School of Medicine
    Inlet and outlet boundary conditions (BCs) play an important role in newly emerged image-based computational hemodynamics for blood flows in human arteries anatomically extracted from medical images. We developed physiological inlet and outlet BCs based on patients’ medical data and integrated them into the volumetric lattice Boltzmann method. The inlet BC is a pulsatile paraboloidal velocity profile, which fits the real arterial shape, constructed from the Doppler velocity waveform. The BC of each outlet is a pulsatile pressure calculated from the three-element Windkessel model, in which three physiological parameters are tuned by the corresponding Doppler velocity waveform. Both velocity and pressure BCs are introduced into the lattice Boltzmann equations through Guo’s non-equilibrium extrapolation scheme. Meanwhile, we performed uncertainty quantification for the impact of uncertainties on the computation results. An application study was conducted for six human aortorenal arterial systems. The computed pressure waveforms have good agreement with the medical measurement data. A systematic uncertainty quantification analysis demonstrates the reliability of the computed pressure with associated uncertainties in the Windkessel model. With the developed physiological BCs, the image-based computation hemodynamics is expected to provide a computation potential for the noninvasive evaluation of hemodynamic abnormalities in diseased human vessels.
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    Inlet and Outlet Boundary Conditions and Uncertainty Quantification in Volumetric Lattice Boltzmann Method for Image-Based Computational Hemodynamics
    (MDPI, 2022) Yu, Huidan; Khan, Monsurul; Wu, Hao; Zhang, Chunze; Du, Xiaoping; Chen, Rou; Fang, Xin; Long, Jianyun; Sawchuk, Alan P.; Mechanical and Energy Engineering, School of Engineering and Technology
    Inlet and outlet boundary conditions (BCs) play an important role in newly emerged image-based computational hemodynamics for blood flows in human arteries anatomically extracted from medical images. We developed physiological inlet and outlet BCs based on patients’ medical data and integrated them into the volumetric lattice Boltzmann method. The inlet BC is a pulsatile paraboloidal velocity profile, which fits the real arterial shape, constructed from the Doppler velocity waveform. The BC of each outlet is a pulsatile pressure calculated from the three-element Windkessel model, in which three physiological parameters are tuned by the corresponding Doppler velocity waveform. Both velocity and pressure BCs are introduced into the lattice Boltzmann equations through Guo’s non-equilibrium extrapolation scheme. Meanwhile, we performed uncertainty quantification for the impact of uncertainties on the computation results. An application study was conducted for six human aortorenal arterial systems. The computed pressure waveforms have good agreement with the medical measurement data. A systematic uncertainty quantification analysis demonstrates the reliability of the computed pressure with associated uncertainties in the Windkessel model. With the developed physiological BCs, the image-based computation hemodynamics is expected to provide a computation potential for the noninvasive evaluation of hemodynamic abnormalities in diseased human vessels.