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  ✔本篇論文使用華聯產品:Human OneArray  
 BMC Bioinformatics. doi: 10.1186/s12859-015-0848-x.
 Gene expression profiling identifies candidate biomarkers for active and latent tuberculosis 
 
  Abstract
Background Tuberculosis (TB) is a serious infectious disease in that 90 % of those latently infected with Mycobacterium tuberculosis present no symptoms, but possess a 10 % lifetime chance of developing active TB. To prevent the spread of the disease, early diagnosis is crucial. However, current methods of detection require improvement in sensitivity, efficiency or specificity. In the present study, we conducted a microarray experiment, comparing the gene expression profiles in the peripheral blood mononuclear cells among individuals with active TB, latent infection, and healthy conditions in a Taiwanese population. Results Bioinformatics analysis revealed that most of the differentially expressed genes belonged to immune responses, inflammation pathways, and cell cycle control. Subsequent RT-PCR validation identified four differentially expressed genes, NEMF, ASUN, DHX29, and PTPRC, as potential biomarkers for the detection of active and latent TB infections. Receiver operating characteristic analysis showed that the expression level of PTPRC may discriminate active TB patients from healthy individuals, while ASUN could differentiate between the latent state of TB infection and healthy condidtion. In contrast, DHX29 may be used to identify latently infected individuals among active TB patients or healthy individuals. To test the concept of using these biomarkers as diagnostic support, we constructed classification models using these candidate biomarkers and found the Naïve Bayes-based model built with ASUN, DHX29, and PTPRC to yield the best performance. Conclusions Our study demonstrated that gene expression profiles in the blood can be used to identify not only active TB patients, but also to differentiate latently infected patients from their healthy counterparts. Validation of the constructed computational model in a larger sample size would confirm the reliability of the biomarkers and facilitate the development of a cost-effective and sensitive molecular diagnostic platform for TB.
   

  ✔本篇論文使用華聯產品:Human OneArray,Human miRNA OneArray  
 BioMed Research International. 2014 July 1.
 Systematic expression profiling analysis identifies specific microRNA-gene interactions that may differentiate between active and latent tuberculosis infection
 
 
 Lawrence Shih-Hsin Wu, Shih-Wei Lee, Kai-Yao Huang, Tzong-Yi Lee, Paul Wei-Che Hsu, Julia Tzu-Ya Weng
  Abstract
Tuberculosis (TB) is the second most common cause of death from infectious diseases. About 90% of those infected are asymptomatic¡Xthe so-called latent TB infections (LTBI), with a 10% lifetime chance of progressing to active TB. In attempt to further understand the molecular pathogenesis of TB and develop efficient diagnostic biomarkers, several molecular studies have attempted to compare the gene and microRNA expression profiles between healthy controls versus active TB or LTBI patients. However, the results vary due to diverse genetic background, study designs, and the inherent complexity of the disease process. Thus, developing a sensitive and efficient method for the detection of LTBI is both crucial and challenging. For the present study, we performed a systematic analysis of the gene and microRNA profiles of healthy individuals versus those affected with TB or LTBI. Combined with a series of in silico analysis utilizing publicly available microRNA knowledge bases and published literature data, we have uncovered several microRNA-gene interactions that specifically target both the blood and lungs, presenting to be useful molecular signatures to help enhance the understanding of TB pathogenesis. Furthermore, some of these molecular interactions are novel, and may serve as potential biomarkers of TB and LTBI, facilitating the development for a more sensitive, efficient, and cost-effective diagnostic assay for TB and LTBI for the Taiwanese population.
   

  ✔本篇論文使用華聯產品:Human OneArray  
 Journal of Biological Chemistry . 2013 Dec 23.
 Anthrax Lethal Toxin Inhibits Translation of Hypoxia Inducible Factor 1£ and Causes Decreased Tolerance to Hypoxic Stress
 
 
 Weiming Ouyang, Chikako Torigoe, Hui Fang, Tao Xie, David M. Frucht
  Abstract
Hypoxia is considered to be a contributor to the pathology associated with administration of anthrax lethal toxin (LT). However, we herein report that serum lactate levels in LT-treated mice are reduced, a finding inconsistent with the anaerobic metabolism expected to occur during hypoxia. Reduced lactate levels are also observed in the culture supernatants of LT-treated cells. LT inhibits the accumulation of hypoxia inducible factor (HIF)-1£, a subunit of HIF-1, the master regulator directing cellular responses to hypoxia. The toxin has no effect on the transcription or protein turnover of HIF-1£, but instead acts to inhibit HIF-1£ translation. LT treatment diminishes phosphorylation of eIF4B, eIF4E, and rpS6, critical components of the intracellular machinery required for HIF-1£ translation. Moreover, blockade of MKK1/2-Erk1/2, but not p38 or JNK signaling lowers HIF-1£ protein levels in both normoxic and hypoxic conditions, consistent with a role for MKK1 and MKK2 as the major targets of LT responsible for the inhibition of HIF-1£ translation. The physiological importance of the LT-induced translation blockade is demonstrated by the finding that LT treatment decreases the survival of hepatocyte cell lines grown in hypoxic conditions, an effect that is overcome by pre-induction of HIF-1£. Taken together, these data support a role for LT in dysregulating HIF-1£ and thereby disrupting homeostatic responses to hypoxia, an environmental characteristic of certain tissues at baseline and/or during disseminated infection with Bacillus anthracis.
   

  ✔本篇論文使用華聯產品:Mouse&Rat miRNA OneArray  
 PLOS ONE. 2013, 8(10): e77936. doi:10.1371/journal.pone.0077936.
 Profiling Circulating MicroRNA Expression in Experimental Sepsis Using Cecal Ligation and Puncture
 
 
 Shao-Chun Wu, Johnson Chia-Shen Yang, Cheng-Shyuan Rau, Yi-Chun Chen, Tsu-Hsiang Lu, Ming-Wei Lin, Siou-Ling Tzeng, Yi-Chan Wu, Chia-Jung Wu, Ching-Hua Hsieh
  Abstract
The levels of circulating microRNAs (miRNAs) in mice with experimental sepsis induced by cecal ligation and puncture (CLP) were determined using whole blood samples obtained from C57BL/6 mice at 4, 8, and 24 h after CLP; miRNA expression analysis was performed in these samples using an miRNA array. Microarray analysis revealed upregulation of 10 miRNA targets (miR-16, miR-17, miR-20a, miR-20b, miR-26a, miR-26b, miR-106a, miR-106b, miR-195, and miR-451). The expression of these miRNA targets in the whole blood, serum, and white blood cells (WBCs) of CLP mice was quantified using quantitative real-time PCR; these values were compared to those in sham-operated C57BL/6 mice, and the results indicated that these miRNA targets were significantly up-regulated in the whole blood and serum but not in the WBCs. In addition, the levels of these 10 miRNA targets in the serum of Tlr2−/−, Tlr4−/−, and NF-£eB−/− mice at 8 h after CLP did not decrease significantly., which indicated that the transcription of these miRNAs was not directly mediated by the TLR2/NF-£eB or TLR4/NF-£eB pathway, and pathways induced by exposure to the gram-positive or gram-negative bacteria. Immunoprecipitation with the Argonaute 2 ribonucleoprotein complex revealed significantly increased expression of the 10 miRNA targets in the serum of mice after CLP, and the levels of 6 (miR-16, miR-17, miR-20a, miR-20b, miR-26a, and miR-26b) of these 10 miRNA targets increased significantly in exosomes isolated using ExoQuick precipitation solution. In this study, we identified circulating miRNAs that were up-regulated after CLP and determined the increase in the levels of these miRNAs, and our results suggest that circulating Ago2 complexes and exosomes may be responsible for the stability of miRNAs in the serum.
   

  ✔本篇論文使用華聯產品:Mouse OneArray  
 Infection, Genetics and Evolution. 2013, 20C:257-269. doi: 10.1016/j.meegid.2013.09.016.
 Global gene expression changes in BV2 microglial cell line during rabies virus infection
 
 
 Zhao P, Yang Y, Feng H, Zhao L, Qin J, Zhang T, Wang H, Yang S, Xia X
  Abstract
Microglia plays a crucial role during virus pathogenesis in the central nervous system (CNS). Infection by rabies virus (RABV) causes a fatal infectionin the CNS of all warm-blooded animals. However, the microglial responses to RABV infection have been scarcely reported. To better understand microglia-RABV interactions at the transcriptional level, a genome wide gene expression profile in mouse microglial cells line BV2 was performed using microarray analysis. The global messenger RNA changes in murine microglial cell line BV2 after 12, 24 and 48h of infection with rabies virusCVS-11 strain were investigated using DNA Microarray and quantitative real-time PCR. Infection of CVS-11 at different time points induced differentgene expression signatures in BV2 cells. The expression patterns of differentially expressed genes are shown by K-means clustering in four clusters in RABV- or mock-infected microglia at 12, 24 and 48h post infection (hpi). Gene ontology and network analysis of the differentially expressed genes in responses to RABV were performed by the Ingenuity Pathway Analysis system (IPA, Ingenuity® Systems, http://www.ingenuity.com). The results revealed that 28 genes were significantly up-regulated (P<0.01) and 1 gene was significantly down-regulated (P<0.01) in microglial cells at 12hpi, 72 genes were significantly up-regulated (P<0.01) and 24 genes were significantly down-regulated (P<0.01) at 24hpi, and 671 genes were significantly up-regulated (P<0.01) and 190 genes were significantly down-regulated (P<0.01) at 48hpi. Genes in BV2 were significantly regulated (P<0.01) in response to RABV infection and they were found to be interferon stimulated genes (Isg15, Isg20, Oasl1, Oasl2, Ifit2, Irf7 and Ifi203), chemokine genes (Ccl5, Cxcl10 and Ccrl2) and the proinflammatory factor gene (Interleukin 6). The results indicated that the differentially expressed genes frommicroglial cells after RABV infection were mainly involved in innate immune responses, inflammatory responses and host antiviral responses.
   

  ✔本篇論文使用華聯產品:Mouse OneArray  
 Cellular Microbiology. 2013 Sep 17. doi: 10.1111/cmi.12216.
 Streptococcal co-infection augments Candida pathogenicity by amplifying the mucosal inflammatory response
 
 
 Xu H, Sobue T, Thompson A, Xie Z, Poon K, Ricker A, Cervantes J, Diaz PI, Dongari-Bagtzoglou A
  Abstract
Mitis-group streptococci are ubiquitous oral commensals that can promote polybacterial biofilm virulence. Using a novel murine oral mucosal co-infection model we sought to determine for the first time whether these organisms promote the virulence of C. albicans mucosal biofilms in oropharyngeal infection and explored mechanisms of pathogenic synergy. We found that Streptococcus oralis colonization of the oral and gastrointestinal tract was augmented in the presence of C. albicans. S. oralis and C. albicans co-infection significantly augmented the frequency and size of oral thrush lesions. Importantly, S. oralis promoted deep organ dissemination of C. albicans. Whole mouse genome tongue microarray analysis showed that when compared with animals infected with one organism, the doubly infected animals had genes in the major categories of neutrophilic response/chemotaxis/inflammation significantly upregulated, indicative of an exaggerated inflammatory response. This response was dependent on TLR2 signalling since oral lesions, transcription of pro-inflammatory genes and neutrophil infiltration, were attenuated in TLR2-/- animals. Furthermore, S. oralis activated neutrophils in a TLR2-dependent manner in vitro. In summary, this study identifies a previously unrecognized pathogenic synergy between oral commensal bacteriaand C. albicans. This is the first report of the ability of mucosal commensal bacteria to modify the virulence of an opportunistic fungal pathogen.
   

  ✔本篇論文使用華聯產品:Mouse OneArray  
 Evidence-Based Complementary and Alternative Medicine. 2013 May 8.
 Phytochemical shikonin stimulates epithelial¡Vmesenchymal transition (EMT) in skin wound-healing
 
 
 Shu-Yi Yin, An-Ping Peng, Li-Ting Huang, Ya-Ting Wang, Chun-Wen Lan, Ning-Sun Yang
  Abstract
Although various pharmacological activities of the shikonins have been documented, understanding of the hierarchical regulation of these diverse bio-activities at the genome level is unsubstantiated. In this study, through cross-examination between transcriptome and microRNA array analyses, we predicted that topical treatment of shikonin in vivo affects epithelial¡Vmesenchymal transition (EMT) and the expression of related microRNAs, including 200a, 200b, 200c, 141, 205 and 429 microRNAs, in mouse skin tissues. In situ immunohistological analyses further demonstrated that specific EMT regulatory molecules are enhanced in shikonin-treated epidermal tissues. RT-PCR analyses subsequently confirmed that shikonin treatment downregulated expression of microRNA-205 and other members of the 200 family microRNAs. Further, expression of two RNA targets of the 200 family microRNAs in EMT regulation, Sip1 (Zeb2) and Tcf8 (Zeb1), were consistently upregulated by shikonin treatment. Enhancement of these EMT activities was also detected in shikonin-treated wounds, which repaired faster than controls. These results suggest that topical treatment with shikonin can confer a potent stimulatory effect on EMT and suppress the expression of the associated microRNAs in skin wound-healing. These cellular and molecular evidences support our previous findings on the specific pharmacological effects of shikonin in wound-healing and immune-modulation.
   

  ✔本篇論文使用華聯產品:Mouse&Rat miRNA OneArray  
 Journal of Biomedical Science. 2013, 20(1):2. doi:10.1186/1423-0127-20-2.
 Circulating microRNA signatures in mice exposed to lipoteichoic acid
 
 
 Ching-Hua Hsieh, Johnson Chia-Shen Yang, Jonathan Chris Jeng, Yi-Chun Chen, Tsu-Hsiang Lu, Siou-Ling Tzeng, Yi-Chan Wu, Chia-Jung Wu, Cheng-Shyuan Rau
  Abstract
BACKGROUND: Previously, we had identified a specific whole blood¡Vderived microRNAs (miRNAs) signature in mice following in vivo injection of lipopolysaccharide (LPS) originated from Gram-negative bacteria. This study was designed to profile the circulating miRNAs expression in mice exposed to lipoteichoic acid (LTA) which is a major component of the wall of Gram-positive bacteria. RESULTS: C57BL/6 mice received intraperitoneal injections of 100 £gg of LTA originated from Bacillus subtilis, Streptococcus faecalis, and Staphylococcus aureus were killed 6 h and the whole blood samples were obtained for miRNA expression analysis using a miRNA array (Phalanx miRNA OneArray 1.0). Up-regulated expression of miRNA targets in the whole blood, serum and white blood cells (WBCs) of C57BL/6 and Tlr2−/− mice upon LTA treatment in 10, 100, or 1000 ug concentrations was quantified at indicated time (2, 6, 24, and 72 h) using real-time RT-PCR and compared with that in the serum of C57BL/6 mice injected with 100 ug of LPS. A significant increase of 4 miRNAs (miR-451, miR-668, miR-1902, and miR-1904) was observed in the whole blood and the serum in a dose- and time-dependent fashion following LTA injection. Induction of miRNA occurred in the serum after 2 h and persisted for at least 6 h. No increased expression of these 4 miRNAs was found in the WBCs. Higher but not significant expression level of these 4 miRNAs were observed following LTA treatment in the serum of Tlr2−/−against that of C57BL6 mice. In contrast, LPS exposure induced moderate expression of miR-451 but not of the other 3 miRNA targets. CONCLUSIONS: We identified a specific circulating miRNA signature in mice exposed to LTA. That expression profile is different from those of mice exposed to LPS. Those circulating miRNAs induced by LTA or LPS treatment may serve as promising biomarkers for the differentiation between exposures to Gram-positive or Gram-negative bacteria.
   

  ✔本篇論文使用華聯產品:Mouse OneArray  
 Virology Journal. 2012, 9:159. doi: 10.1186/1743-422X-9-159.
 Infection with street strain rabies virus induces modulation of the microRNA profile of the mouse brain
 
 
 Pingsen Zhao, Lili Zhao, Kun Zhang, Hao Feng, Hualei Wang, Tiecheng Wang, Tao Xu, Na Feng, Chengyu Wang, Yuwei Gao, Geng Huang, Chuan Qin, Songtao Yang, Xianzhu Xia
  Abstract
Rabies virus (RABV) causes a fatal infection of the central nervous systems (CNS) of warm-blooded animals. Once the clinical symptoms develop, rabies is almost invariably fatal. The mechanism of RABV pathogenesis remains poorly understood. Recent studies have shown that microRNA (miRNA) plays an important role in the pathogenesis of viral infections. Our recent findings have revealed that infection with laboratory-fixed rabies virus strain can induce modulation of the microRNA profile of mouse brains. However, no previous report has evaluated the miRNA expression profile of mouse brains infected with RABV street strain. The results of microarray analysis show that miRNA expression becomes modulated in the brains of mice infected with street RABV. Quantitative real-time PCR assay of the differentially expressed miRNAs confirmed the results of microarray assay. Functional analysis showed the differentially expressed miRNAs to be involved in many immune-related signaling pathways, such as the Jak-STAT signaling pathway, the MAPK signaling pathway, cytokine-cytokine receptor interactions, and Fc gamma R-mediated phagocytosis. The predicted expression levels of the target genes of these modulated miRNAs were found to be correlated with gene expression as measured by DNA microarray and qRT-PCR. RABV causes significant changes in the miRNA expression profiles of infected mouse brains. Predicted target genes of the differentially expression miRNAs are associated with host immune response, which may provide important information for investigation of RABV pathogenesis and therapeutic method.
   

  ✔本篇論文使用華聯產品:Mouse&Rat miRNA OneArray  
 Journal of Biomedical Science. 2012, 19:69. doi: 10.1186/1423-0127-19-69.
 Whole blood-derived microRNA signatures in mice exposed to lipopolysaccharides
 
 
 Ching-Hua Hsieh, Cheng-Shyuan Rau, Jonathan Chris Jeng, Yi-Chun Chen, Tsu-Hsiang Lu, Chia-Jung Wu, Yi-Chan Wu, Siou-Ling Tzeng, Johnson Chia-Shen Yang
  Abstract
Lipopolysaccharide (LPS) is recognized as the most potent microbial mediator presaging the threat of invasion of Gram-negative bacteria that implicated in the pathogenesis of sepsis and septic shock. This study was designed to examine the microRNA (miRNA) expression in whole blood from mice injected with intraperitoneal LPS. C57BL/6 mice received intraperitoneal injections of varying concentrations (range, 10¡V1000 £gg) of LPS from different bacteria, including Escherichia coli, Klebsiella pneumonia, Pseudomonas aeruginosa, Salmonella enterica, and Serratia marcescens and were killed 2, 6, 24, and 72 h after LPS injection. Whole blood samples were obtained and tissues, including lung, brain, liver, and spleen, were harvested for miRNA expression analysis using an miRNA array (Phalanx miRNA OneArrayR 1.0). Upregulated expression of miRNA targets in the whole blood of C57BL/6 and Tlr4?/? mice injected with LPS was quantified using real-time RT-PCR and compared with that in the whole blood of C57BL/6 mice injected with lipoteichoic acid (LTA) from Staphylococcus aureus. Following LPS injection, a significant increase of 15 miRNAs was observed in the whole blood. Among them, only 3 miRNAs showed up-regulated expression in the lung, but no miRNAs showed a high expression level in the other examined tissues. Upregulated expression of the miRNA targets (let-7d, miR-15b, miR-16, miR-25, miR-92a, miR-103, miR-107 and miR-451) following LPS injection on real-time RT-PCR was dose- and time-dependent. miRNA induction occurred after 2 h and persisted for at least 6 h. Exposure to LPS from different bacteria did not induce significantly different expression of these miRNA targets. Additionally, significantly lower expression levels of let-7d, miR-25, miR-92a, miR-103, and miR-107 were observed in whole blood of Tlr4?/? mice. In contrast, LTA exposure induced moderate expression of miR-451 but not of the other 7 miRNA targets. We identified a specific whole blood¡Vderived miRNA signature in mice exposed to LPS, but not to LTA, from different gram-negative bacteria. These whole blood-derived miRNAs are promising as biomarkers for LPS exposure.
   

  ✔本篇論文使用華聯產品:Experimental Accessories  
 BMC Microbiology. 2012, 12:87. doi: 10.1186/1471-2180-12-87.
 Gene expression profiling of Mycobacterium avium subsp. paratuberculosis in simulated multi-stress conditions and within THP-1 cells reveals a new kind of interactive intramacrophage behaviour
 
 
 Leonardo A Sechi, Stefania Zanetti, Valentina Rosu, Andrea Cossu
  Abstract
Recent studies have identified in Mycobacterium avium subsp. paratuberculosis (MAP), already known as a pathogen in ruminants, a potential zoonotic agent of some autoimmune diseases in humans. Therefore, considering the possible risk for public health, it is necessary a thorough understanding of MAP's gene expression during infection of human host as well as the identification of its immunogenic and/or virulence factors for the development of appropriate diagnostic and therapeutic tools. In order to characterize MAP's transcriptome during macrophage infection, we analyzed for the first time the whole gene expression of a human derived strain of MAP in simulated intraphagosomal conditions and after intracellular infection of the human macrophage cell line THP-1 by using the DNA-microarray technology. Results showed that MAP shifts its transcriptome to an adaptive metabolism for an anoxic environment and nutrient starvation. It up-regulates several response factors to oxidative stress or intracellular conditions and allows, in terms of transcription, a passive surface peptidoglycan spoliation within the macrophage along with an intensification of the anabolic activity for lipidic membrane structures. These results indicate a possible interactive system between MAP and its host cell based on the internal mimicry unlike other intracellular pathogens, bringing new hypothesis in the virulence and pathogenicity of MAP and its importance in human health.
   

  ✔本篇論文使用華聯產品:Human OneArray  
 Cell. 2011, 147(2):436-46. doi: 10.1016/j.cell.2011.09.022.
 Activation of STAT6 by STING Is Critical for Antiviral Innate Immunity
 
 
 Huihui Chen, Hui Sun, Fuping You, Wenxiang Sun, Xiang Zhou, Lu Chen, Jing Yang, Yutao Wang, Hong Tang, Yukun Guan, Weiwei Xia, Jun Gu, Hiroki Ishikawa, Delia Gutman, Glen Barber, Zhihai Qin, Zhengfan Jiang
  Abstract
STAT6 plays a prominent role in adaptive immunity by transducing signals from extracellular cytokines. We now show that STAT6 is required for innate immune signaling in response to virus infection. Viruses or cytoplasmic nucleic acids trigger STING (also named MITA/ERIS) to recruit STAT6 to the endoplasmic reticulum, leading to STAT6 phosphorylation on Ser(407) by TBK1 and Tyr(641), independent of JAKs. Phosphorylated STAT6 then dimerizes and translocates to the nucleus to induce specific target genes responsible for immune cell homing. Virus-induced STAT6 activation is detected in all cell-types tested, in contrast to the cell-type specific role of STAT6 in cytokine signaling, and Stat6(-/-) mice are susceptible to virus infection. Thus, STAT6 mediates immune signaling in response to both cytokines at the plasma membrane, and virus infection at the endoplasmic reticulum.
   

  ✔本篇論文使用華聯產品:Mouse OneArray  
 Microbial Pathogenesis. 2012, 52(1):47-54. doi: 10.1016/j.micpath.2011.10.001.
 Changes in microRNA expression induced by rabies virus infection in mouse brains
 
 
 Pingsen Zhao, Lili Zhao, Tao Zhang, Hualei Wang, Chuan Qin, Songtao Yang, Xianzhu Xia
  Abstract
MicroRNAs (miRNAs) are small RNA (? 22 nt) molecules expressed endogenously in cells. They are involved in the regulation of gene expression. Recently, evidence has shown that cellular miRNAs have key regulatory roles in virus-host interactions. The rabies virus (RABV) causes a fatal infection of the central nervous systems (CNS) of warm-blooded animals, yet its pathogenesis remains poorly understood. To gain more insight into the pathogenesis of RABV, a miRNA microarray was performed as part of an investigation of changes in host miRNA expression in the brains of mice infected with RABV. The results showed that RABV infection induced modulation of the expression of sixteen miRNA molecules. These data were verified by real-time PCR. Functional analysis showed the differentially expressed miRNAs to be involved in many immune-related signaling pathways, such as the RIG-I-like receptor signaling pathway, JAK-STAT signaling pathway, chemokine signaling pathway, T-cell receptor signaling pathway, MAPK signaling pathway, leukocyte transendothelial migration, and natural killer cell mediated cytotoxicity. The predicted expression levels of the target genes of these modulated miRNAs correlated with measurements of gene expression measured by DNA microarray and qRT-PCR.
   

  ✔本篇論文使用華聯產品:Human OneArray  
 The Journal of Biological Chemistry. 2011, 286(25):22211-8. doi: 10.1074/jbc.M110.180224.
 Inhibitors of histone deacetylases: correlation between isoform specificity and reactivation of HIV type 1 (HIV-1) from latently infected cells.
 
 
 Huber K, Doyon G, Plaks J, Fyne E, Mellors JW, Sluis-Cremer N.
  Abstract
Deacetylation of histone proteins at the HIV type 1 (HIV-1) long terminal repeat (LTR) by histone deactylases (HDACs) can promote transcriptional repression and virus latency. As such, HDAC inhibitors (HDACI) could be used to deplete reservoirs of persistent, quiescent HIV-1 proviral infection. However, the development of HDACI to purge latent HIV-1 requires knowledge of the HDAC isoforms contributing to viral latency and the development of inhibitors specific to these isoforms. In this study, we identify the HDACs responsible for HIV-1 latency in Jurkat J89GFP cells using a chemical approach that correlates HDACI isoform specificity with their ability to reactivate latent HIV-1 expression. We demonstrate that potent inhibition or knockdown of HDAC1, an HDAC isoform reported to drive HIV-1 into latency, was not sufficient to de-repress the viral LTR. Instead, we found that inhibition of HDAC3 was necessary to activate latent HIV-1. Consistent with this finding, we identified HDAC3 at the HIV-1 LTR by chromatin immunoprecipitation. Interestingly, we show that valproic acid is a weak inhibitor of HDAC3 (IC(50) = 5.5 mm) relative to HDAC1 (IC(50) = 170 £gm). Because the total therapeutic concentration of valproic acid ranges from 275 to 700 £gm in adults, these data may explain why this inhibitor has no effect on the decay of latent HIV reservoirs in patients. Taken together, our study suggests an important role for HDAC3 in HIV-1 latency and, importantly, describes a chemical approach that can readily be used to identify the HDAC isoforms that contribute to HIV-1 latency in other cell types.
   

  ✔本篇論文使用華聯產品:Human OneArray  
 J. Virol. 2011, 85(18):9268-75. doi: 10.1128/JVI.00772-11.
 GFP Reporter System with Transcriptional Sequence Heterogeneity for Monitoring Interferon Response
 
 
 Mahmoud L, Al-Saif M, Amer HM, Sheikh M, Almajhdi FN, Khabar KS.
  Abstract
The interferon (IFN) response is initiated by a variety of triggers, including viruses and foreign RNA, and involves several receptors and intracellular mediators. Although there are common cis-acting consensus sequences in the promoters of many genes stimulated during the IFN response, they exhibit core and context heterogeneity that may lead to differential transcriptional activity. We have developed and validated a live cell-based enhanced green fluorescent protein (EGFP) reporter system employing more than a hundred constructs containing multiple viruses and IFN response elements derived from a variety of promoters involved in immunity to viruses. Common and distinct response patterns were observed due to promoter heterogeneity in response to different stimuli, including IFN-£, TLR3-agonist double-stranded RNA, and several viruses. This information should serve as a resource in selecting specific reporters for sensing nonself ligands.
   

  ✔本篇論文使用華聯產品:Human OneArray  
 J Immunology. 2011, 186(3):1638-45. doi: 10.4049/jimmunol.1003146.
 c-Maf-dependent growth of Mycobacterium tuberculosis in a CD14(hi) subpopulation of monocyte-derived macrophages
 
 
 Dhiman R, Bandaru A, Barnes PF, Saha S, Tvinnereim A, Nayak RC, Paidipally P, Valluri VL, Rao LV, Vankayalapati R.
  Abstract
Macrophages are a major component of the innate immune response, comprising the first line of defense against various intracellular pathogens, including Mycobacterium tuberculosis. In this report, we studied the factors that regulate growth of M. tuberculosis H37Rv in subpopulations of human monocyte-derived macrophages (MDMs). In healthy donors, M. tuberculosis H37Rv grew 5.6-fold more rapidly in CD14(hi) MDMs compared with that in CD14(lo)CD16(+) MDMs. Compared with CD14(lo)CD16(+) cells, M. tuberculosis H37Rv-stimulated CD14(hi) monocytes produced more IL-10 and had increased mRNA expression for c-Maf, a transcription factor that upregulates IL-10 gene expression. c-Maf small interfering RNA (siRNA) inhibited IL-10 production and growth of M. tuberculosis in CD14(hi) cells. Compared with CD14(lo)CD16(+) monocytes, M. tuberculosis H37Rv-stimulated CD14(hi) cells had increased expression of 22 genes whose promoters contained a c-Maf binding site, including hyaluronan synthase 1 (HAS1). c-Maf siRNA inhibited HAS1 expression in M. tuberculosis-stimulated CD14(hi) monocytes, and HAS1 siRNA inhibited growth of M. tuberculosis in CD14(hi) MDMs. M. tuberculosis H37Rv upregulated expression of HAS1 protein and its product, hyaluronan, in CD14(hi) MDMs. We conclude that M. tuberculosis grows more rapidly in CD14(hi) than in CD14(lo)CD16(+) MDMs because CD14(hi) cells have increased expression of c-Maf, which increases production of two key factors (hyaluronan and IL-10) that promote growth of M. tuberculosis.
   

  ✔本篇論文使用華聯產品:Human OneArray  
 J Infect Dis. 2010, 202(2):282-90. doi: 10.1086/653484.
 Transcriptional profiling of Clostridium difficile and Caco-2 cells during infection
 
 
 Janvilisri T, Scaria J, Chang YF.
  Abstract
Clostridium difficile is well recognized as the most common infectious cause of nosocomial diarrhea. The incidence and severity of C. difficile infection (CDI) is increasing worldwide. Here, we evaluated simultaneously the transcriptional changes in the human colorectal epithelial Caco-2 cells and in C. difficile after infection. A total of 271 transcripts in Caco-2 cells and 207 transcripts in C. difficile were significantly differentially expressed at 1 time point during CDI. We used the gene ontology annotations and protein-protein network interactions to underline a framework of target molecules that could potentially play a key role during CDI. These genes included those associated with cellular metabolism, transcription, transport, cell communication, and signal transduction. Our data identified certain key factors that have previously been reported to be involved in CDI, as well as novel determinants that may participate in a complex mechanism underlying the host response to infection, bacterial adaptation, and pathogenesis.
   

  ✔本篇論文使用華聯產品:Human OneArray  
 BMC Microbiology. 2010, 10:244. doi: 10.1186/1471-2180-10-244.
 Coxiella burnetii Nine Mile II proteins modulate gene expression of monocytic host cells during infection.
 
 
 Saugata Mahapatra, Patricia Ayoubi, Edward I Shaw.
  Abstract
Coxiella burnetii is an intracellular bacterial pathogen that causes acute and chronic disease in humans. Bacterial replication occurs within enlarged parasitophorous vacuoles (PV) of eukaryotic cells, the biogenesis and maintenance of which is dependent on C. burnetii protein synthesis. These observations suggest that C. burnetii actively subverts host cell processes, however little is known about the cellular biology mechanisms manipulated by the pathogen during infection. Here, we examined host cell gene expression changes specifically induced by C. burnetii proteins during infection. We have identified 36 host cell genes that are specifically regulated when de novo C. burnetii protein synthesis occurs during infection using comparative microarray analysis. Two parallel sets of infected and uninfected THP-1 cells were grown for 48 h followed by the addition of chloramphenicol (CAM) to 10 £gg/ml in one set. Total RNA was harvested at 72 hpi from all conditions, and microarrays performed using Phalanx Human OneArray? slides. A total of 784 (mock treated) and 901 (CAM treated) THP-1 genes were up or down regulated ?2 fold in the C. burnetii infected vs. uninfected cell sets, respectively. Comparisons between the complementary data sets (using >0 fold), eliminated the common gene expression changes. A stringent comparison (?2 fold) between the separate microarrays revealed 36 host cell genes modulated by C. burnetii protein synthesis. Ontological analysis of these genes identified the innate immune response, cell death and proliferation, vesicle trafficking and development, lipid homeostasis, and cytoskeletal organization as predominant cellular functions modulated by C. burnetii protein synthesis. Collectively, these data indicate that C. burnetii proteins actively regulate the expression of specific host cell genes and pathways. This is in addition to host cell genes that respond to the presence of the pathogen whether or not it is actively synthesizing proteins. These findings indicate that C. burnetii modulates the host cell gene expression to avoid the immune response, preserve the host cell from death, and direct the development and maintenance of a replicative PV by controlling vesicle formation and trafficking within the host cell during infection.
   

  ✔本篇論文使用華聯產品:Human OneArray  
 International Journal of Food Microbiology. 2009, 131(2-3):224-32. doi: 10.1016/j.ijfoodmicro.2009.03.002.
 Interactive transcriptome analysis of enterohemorrhagic Escherichia coli+H23 (EHEC) O157:H7 and intestinal epithelial HT-29 cells after bacterial attachment.
 
 
 Younghoon Kim , Sejong Oh , Sungsu Park , Sae Hun Kim.
  Abstract
Here, the gene expression profiles of EHEC O157:H7 and HT-29 during the attachment stage were investigated by using duplex whole transcriptome analysis. After the initial attachment (3 h), the gene regulation systems of both the EHEC O157:H7 and HT-29 host cells were immediately remodeled. A total of 326 genes of the HT-29 cells, which involved proteins associated with the detoxification process, stress response proteins, anti-apoptosis/inflammation proteins, immune response protein, and oxidative stress proteins, were differentially regulated by more than 2.0-fold during EHEC attachment. In contrast, when HT-29 was attached to EHEC the expression of 611 genes was induced and the expression of 384 genes was reduced by more than twofold when compared to RPMI 1640-grown EHEC (16.14% of the total hybridized genes). Among the genes that were classified according to biological function, the mRNA levels of the genes involved in stress response, oxidative stress, cell signaling and cell surface proteins were significantly altered after the attachment of EHEC O157:H7. Therefore, the results of this study provide crucial insight into the genetic networks that provide host cell protection and the strategy of EHEC O157:H7 pathogenesis in gastro-intestinal (GI) tracts.