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author:("Wu, huiquan")
1.  Increased Frequency of Tim-3 Expressing T Cells Is Associated with Symptomatic West Nile Virus Infection 
PLoS ONE  2014;9(3):e92134.
More than a decade after West Nile virus (WNV) entered North America, and despite a significant increase in reported cases during the 2012 and 2013 seasons, no treatment or vaccine for humans is available. Although antiviral T cells contribute to the control of WNV, little is known about their regulation during acute infection. We analyzed the expression of Tim-3 and PD-1, two recently identified T cell negative immune checkpoint receptors, over the course of WNV infection. Symptomatic WNV+ donors exhibited higher frequencies of Tim-3+ cells than asymptomatic subjects within naïve/early differentiated CD28+/–CD57–CD4+ and differentiated CD28–CD57–CD8+ T cells. Our study links Tim-3-expression on T cells during acute WNV infection with the development of symptomatic disease, suggesting Tim-3 and its ligands could be targeted therapeutically to alter anti-WNV immunity and improve disease outcome.
doi:10.1371/journal.pone.0092134
PMCID: PMC3958446  PMID: 24642562
2.  Transcriptional Response of Ex Vivo Human Skin to Ionizing Radiation: Comparison Between Low- and High-Dose Effects 
Radiation research  2011;177(1):69-83.
Although human exposure to low-dose ionizing radiation can occur through a variety of sources, including natural, medical, occupational and accidental, the true risks of low-dose ionizing radiation are still poorly understood in humans. Here, the global transcriptional responses of human skin after ex vivo exposure to low (0.05 Gy) and high (5 Gy) doses of X rays and of time in culture (0 Gy) at 0, 2, 8 and 30 h postirradiation were analyzed and compared. Responses to low and high doses differed quantitatively and qualitatively. Differentially expressed genes fell into three groups: (1) unique genes defined as responsive to either 0.05 or 5 Gy but not both and also responsive to time in culture, (2) specific genes defined as responsive to either 0.05 or 5 Gy but not both and not responsive to time in culture, and (3) dose-independent responsive genes. Major differences observed in ex vivo irradiated skin between transcriptional responses to low or high doses were twofold. First, gene expression modulated by 0.05 Gy was transient, while in response to 5 Gy persistence of modified gene expression was observed for a limited number of genes. Second, neither TP53 nor TGFβ target genes were modulated after exposure to an acute low dose, suggesting that the TP53-dependent DNA damage response either was not triggered or was triggered only briefly.
PMCID: PMC3549263  PMID: 22029842
3.  The effect of HIV infection and HAART on inflammatory biomarkers in a population-based cohort of US women 
AIDS (London, England)  2011;25(15):1823-1832.
Objective
HIV causes inflammation that can be at least partially corrected by HAART. To determine the qualitative and quantitative nature of cytokine perturbation, we compared cytokine patterns in three HIV clinical groups including HAART responders (HAART), untreated HIV non-controllers (NC), and HIV-uninfected (NEG).
Methods
Multiplex assays were used to measure 32 cytokines in a cross-sectional study of participants in the Women's Interagency HIV Study (WIHS). Participants from 3 groups were included: HAART (n=17), NC (n=14), and HIV NEG (n=17).
Results
Several cytokines and chemokines showed significant differences between NC and NEG participants, including elevated IP-10 and TNF-α and decreased IL-12(p40), IL-15, and FGF-2 in NC participants. Biomarker levels among HAART women more closely resembled the NEG, with the exception of TNF-α and FGF-2. Secondary analyses of the combined HAART and NC groups revealed that IP-10 showed a strong, positive correlation with viral load and negative correlation with CD4+ T cell counts. The growth factors VEGF, EGF, and FGF-2 all showed a positive correlation with increased CD4+ T cell counts.
Conclusion
Untreated, progressive HIV infection was associated with decreased serum levels of cytokines important in T cell homeostasis (IL-15) and T cell phenotype determination (IL-12), and increased levels of innate inflammatory mediators such as IP-10 and TNF-α. HAART was associated with cytokine profiles that more closely resembled those of HIV uninfected women. The distinctive pattern of cytokine levels in the 3 study groups may provide insights into HIV pathogenesis, and responses to therapy.
doi:10.1097/QAD.0b013e3283489d1f
PMCID: PMC3314300  PMID: 21572306
HIV; CD4+ T cells; cytokines; chemokines; HAART
4.  Genomic characterization of a three-dimensional skin model following exposure to ionizing radiation 
Journal of Radiation Research  2012;53(6):860-875.
This study aimed at characterizing the genomic response to low versus moderate doses of ionizing radiation (LDIR versus MDIR) in a three-dimensional (3D) skin model, which exhibits a closer tissue complexity to human skin than monolayer cell cultures. EpiDermFT skin plugs were exposed to 0, 0.1 and 1 Gy doses of X-rays and harvested at 5 min, 3, 8 and 24 h post-irradiation (post-IR). RNA was interrogated for global gene expression alteration. Our results show that MDIR modulated a larger number of genes over the course of 24 h compared to LDIR. However, immediately and throughout the first 3h post-IR, LDIR modulated a larger number of genes than MDIR, mostly associated with cell–cell signaling and survival promotion. Significant modulation of pathways was detected only at 3 h post-IR in MDIR with induction of genes promoting apoptosis. Collectively, the data show different dynamics in the response to LDIR versus MDIR, especially in cell-cycle distribution. LDIR-exposed tissues showed signs of attempted cell-cycle re-entry as early as 3 h post-IR, but were arrested beyond 8 h at the G1/S checkpoint. At 24 h, cells appeared to accumulate at the G2/M checkpoint. MDIR-exposed tissues did not exhibit a prolonged G1/S arrest but rather a prolonged G2/M arrest, which was sustained at least up to 24 h. By 24 h cells exhibited signs of recovery in both LDIR- and MDIR-exposed tissues. In summary, the most pronounced difference in the initial cellular response to LDIR versus MDIR is the promotion of protection and survival in LDIR versus the promotion of apoptosis in MDIR.
doi:10.1093/jrr/rrs063
PMCID: PMC3483859  PMID: 22915785
low dose ionizing radiation; EpiDermFT; gene expression; microarray
5.  Association between HLA Class I and Class II Alleles and the Outcome of West Nile Virus Infection: An Exploratory Study 
PLoS ONE  2011;6(8):e22948.
Background
West Nile virus (WNV) infection is asymptomatic in most individuals, with a minority developing symptoms ranging from WNV fever to serious neuroinvasive disease. This study investigated the impact of host HLA on the outcome of WNV disease.
Methods
A cohort of 210 non-Hispanic mostly white WNV+ subjects from Canada and the U.S. were typed for HLA-A, B, C, DP, DQ, and DR. The study subjects were divided into three WNV infection outcome groups: asymptomatic (AS), symptomatic (S), and neuroinvasive disease (ND). Allele frequency distribution was compared pair-wise between the AS, S, and ND groups using χ2 and Fisher's exact tests and P values were corrected for multiple comparisons (Pc). Allele frequencies were compared between the groups and the North American population (NA) used as a control group. Logistic regression analysis was used to evaluate the potential synergistic effect of age and HLA allele phenotype on disease outcome.
Results
The alleles HLA-A*68, C*08 and DQB*05 were more frequently associated with severe outcomes (ND vs. AS, PA*68 = 0.013/Pc = 0.26, PC*08 = 0.0075/Pc = 0.064, and PDQB1*05 = 0.029/Pc = 0.68), However the apparent DQB1*05 association was driven by age. The alleles HLA-B*40 and C*03 were more frequently associated with asymptomatic outcome (AS vs. S, PB*40 = 0.021/Pc = 0.58 and AS vs. ND PC*03 = 0.039/Pc = 0.64) and their frequencies were lower within WNV+ subjects with neuroinvasive disease than within the North American population (NA vs. S, PB*40 = 0.029 and NA vs. ND, PC*03 = 0.032).
Conclusions
Host HLA may be associated with the outcome of WNV disease; HLA-A*68 and C*08 might function as “susceptible” alleles, whereas HLA-B*40 and C*03 might function as “protective” alleles.
doi:10.1371/journal.pone.0022948
PMCID: PMC3148246  PMID: 21829673

Results 1-5 (5)