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Find video protocols related to scientific articles indexed in Pubmed.
PARP-14 combines with tristetraprolin in the selective post-transcriptional control of macrophage tissue factor expression.
Blood
PUBLISHED: 10-09-2014
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Tissue factor (TF, CD142) is a 47 kDa transmembrane cell surface glycoprotein which triggers the extrinsic coagulation cascade and links thrombosis with inflammation. Although macrophage TF expression is known to be regulated at the RNA level, very little is known about the mechanisms involved. Poly(ADP-ribose)-polymerase (PARP)-14 belongs to a family of intracellular proteins that generate ADP-ribose post-translational adducts. Functional screening of PARP-14 deficient macrophages mice revealed that PARP-14 deficiency leads to increased tissue factor (TF) expression and functional activity in macrophages following challenge with bacterial lipopolysaccharide. This was related to an increase in TF mRNA stability. Ribonucleoprotein complex immunoprecipitation and biotinylated RNA pull-down assays demonstrated that PARP-14 forms a complex with the mRNA-destabilizing protein tristetraprolin (TTP) and a conserved AU-rich element in the TF mRNA 3' untranslated region. TF mRNA regulation by PARP-14 was selective, as TNF? mRNA, which is also regulated by TTP, was not altered in PARP-14 deficient macrophages. Consistent with the in vitro data, TF expression and TF activity, but not TNF? expression, were increased in Parp14(-/-) mice in vivo. Our study provides a novel mechanism for the post-transcriptional regulation of TF expression, indicating that this is selectively regulated by PARP-14.
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Selective tumor necrosis factor receptor I blockade is antiinflammatory and reveals immunoregulatory role of tumor necrosis factor receptor II in collagen-induced arthritis.
PUBLISHED: 06-17-2014
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Tumor necrosis factor (TNF) signals via 2 receptors, TNFR type I (TNFRI) and TNFRII, with distinct cellular distribution and signaling functions. In rheumatoid arthritis (RA), the net effect of TNFR signaling favors inflammatory responses while inhibiting the activity of regulatory T cells. TNFRII signaling has been shown to promote Treg cell function. To assess the relative contributions of TNFRI and TNFRII signaling to inflammatory and regulatory responses in vivo, we compared the effect of TNF blockade, hence TNFRI/II, versus TNFRI alone in collagen-induced arthritis (CIA) as a model of RA.
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TNFR2 increases the sensitivity of ligand-induced activation of the p38 MAPK and NF-?B pathways and signals TRAF2 protein degradation in macrophages.
Cell. Signal.
PUBLISHED: 10-29-2013
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Tumour necrosis factor (p55 or p60) receptor (TNFR)1 is the major receptor that activates pro-inflammatory signalling and induces gene expression in response to TNF. Consensus is lacking for the function of (p75 or p80) TNFR2 but experiments in mice have suggested neuro-, cardio- and osteo- protective and anti-inflammatory roles. It has been shown in various cell types to be specifically required for the induction of TNFR-associated factor-2 (TRAF2) degradation, activation of the alternative nuclear factor (NF)-kappaB pathway, and to contribute to the activation of mitogen-activated protein kinases (MAPK) and the classical NF-kappaB pathway. We have investigated the signalling functions of TNFR2 in primary human and murine macrophages. We find that in these cells TNF induces TRAF2 degradation, and this is blocked in TNFR2(-/-) macrophages. TRAF2 has been previously reported to be required for TNF-induced activation of p38 MAPK. However, TRAF2 degradation does not inhibit TNF-induced tolerance of p38 MAPK activation. Neither TNF, nor lipopolysaccharide treatment, induced activation of the alternative NF-kappaB pathway in macrophages. Activation by TNF of the p38 MAPK and NF-kappaB pathways was blocked in TNFR1(-/-) macrophages. In contrast, although TNFR2(-/-) macrophages displayed robust p38 MAPK activation and IkappaB? degradation at high concentrations of TNF, at lower doses the concentration dependence of signalling was weakened by an order of magnitude. Our results suggest that, in addition to inducing TRAF2 protein degradation, TNFR2 also plays a crucial auxiliary role to TNFR1 in sensitising macrophages for the ligand-induced activation of the p38 MAPK and classical NF-kappaB pro-inflammatory signalling pathways.
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Cross talk between the Akt and p38? pathways in macrophages downstream of Toll-like receptor signaling.
Mol. Cell. Biol.
PUBLISHED: 08-26-2013
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The stimulation of Toll-like receptors (TLRs) on macrophages by pathogen-associated molecular patterns (PAMPs) results in the activation of intracellular signaling pathways that are required for initiating a host immune response. Both phosphatidylinositol 3-kinase (PI3K)-Akt and p38 mitogen-activated protein kinase (MAPK) signaling pathways are activated rapidly in response to TLR activation and are required to coordinate effective host responses to pathogen invasion. In this study, we analyzed the role of the p38-dependent kinases MK2/3 in the activation of Akt and show that lipopolysaccharide (LPS)-induced phosphorylation of Akt on Thr308 and Ser473 requires p38? and MK2/3. In cells treated with p38 inhibitors or an MK2/3 inhibitor, phosphorylation of Akt on Ser473 and Thr308 is reduced and Akt activity is inhibited. Furthermore, BMDMs deficient in MK2/3 display greatly reduced phosphorylation of Ser473 and Thr308 following TLR stimulation. However, MK2/3 do not directly phosphorylate Akt in macrophages but act upstream of PDK1 and mTORC2 to regulate Akt phosphorylation. Akt is recruited to phosphatidylinositol 3,4,5-trisphosphate (PIP3) in the membrane, where it is activated by PDK1 and mTORC2. Analysis of lipid levels in MK2/3-deficient bone marrow-derived macrophages (BMDMs) revealed a role for MK2/3 in regulating Akt activity by affecting availability of PIP3 at the membrane. These data describe a novel role for p38?-MK2/3 in regulating TLR-induced Akt activation in macrophages.
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Increased levels of PD-1 expression on CD8 T cells in patients post-renal transplant irrespective of chronic high EBV viral load.
Pediatr Transplant
PUBLISHED: 08-16-2013
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Studies have identified solid organ transplant recipients who remain asymptomatic despite maintaining CHL. Factors which determine the CHL state remain poorly understood but are likely to involve immunological control of the viral infection. We monitored expression of PD-1, a marker of T-cell exhaustion and viral persistence, on CD8 T cells in patients who resolved EBV infection as determined by undetectable EBV DNA (REI) and CHL patients. PD-1 expression on CD8 T cells was increased in the first year post-transplant irrespective of EBV outcome, and most CD8 T cells continued to express PD-1 for up to three yr post-transplant. Although all patient groups showed similar frequencies of EBV-specific CD8+ T cells, PD-1 expression on these cells increased in the post-transplant groups compared with the pretransplant patients. Functional studies of EBV-specific CD8+ T cells stimulated with BZLF or LMP2 peptide pools revealed monofunctional IFN-? responses. Our results indicate that PD-1 expression on CD8 T cells post-transplant may result from factors other than antigenic stimulation.
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Evidence of enhanced systemic inflammation in stable kidney transplant recipients with low Framingham risk scores.
Clin Transplant
PUBLISHED: 04-10-2013
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While the Framingham risk score (FRS) predicts cardiovascular risk in the general population, it underestimates cardiovascular events in renal transplant recipients (RTR). Inflammation is common in RTR, and it is also a hallmark of vascular injury contributing to cardiovascular events.
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Cezanne regulates inflammatory responses to hypoxia in endothelial cells by targeting TRAF6 for deubiquitination.
Circ. Res.
PUBLISHED: 04-05-2013
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Hypoxia followed by reoxygenation promotes inflammation by activating nuclear factor ?B transcription factors in endothelial cells (ECs). This process involves modification of the signaling intermediary tumor necrosis factor receptor-associated factor 6 with polyubiquitin chains. Thus, cellular mechanisms that suppress tumor necrosis factor receptor-associated factor 6 ubiquitination are potential therapeutic targets to reduce inflammation in hypoxic tissues.
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MSK1 and MSK2 inhibit lipopolysaccharide-induced prostaglandin production via an interleukin-10 feedback loop.
Mol. Cell. Biol.
PUBLISHED: 02-04-2013
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Prostaglandin production is catalyzed by cyclooxygenase 2 (cox-2). We demonstrate here that MSK1 and MSK2 (MSK1/2) can exert control on the induction of cox-2 mRNA by Toll-like receptor (TLR) agonists. In the initial phase of cox-2 induction, MSK1/2 knockout macrophages confirmed a role for MSK in the positive regulation of transcription. However, at later time points both lipopolysaccharide (LPS)-induced prostaglandin and cox-2 protein levels were increased in MSK1/2 knockout. Further analysis found that while MSKs promoted cox-2 mRNA transcription, following longer LPS stimulation MSKs also promoted degradation of cox-2 mRNA. This was found to be the result of an interleukin 10 (IL-10) feedback mechanism, with endogenously produced IL-10 promoting cox-2 degradation. The ability of IL-10 to do this was dependent on the mRNA binding protein TTP through a p38/MK2-mediated mechanism. As MSKs regulate IL-10 production in response to LPS, MSK1/2 knockout results in reduced IL-10 secretion and therefore reduced feedback from IL-10 on cox-2 mRNA stability. Following LPS stimulation, this increased mRNA stability correlated to an elevated induction of both of cox-2 protein and prostaglandin secretion in MSK1/2 knockout macrophages relative to that in wild-type cells. This was not restricted to isolated macrophages, as a similar effect of MSK1/2 knockout was seen on plasma prostaglandin E2 (PGE2) levels following intraperitoneal injection of LPS.
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Heat shock protein B1-deficient mice display impaired wound healing.
PLoS ONE
PUBLISHED: 01-01-2013
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There is large literature describing in vitro experiments on heat shock protein (hsp)B1 but understanding of its function in vivo is limited to studies in mice overexpressing human hspB1 protein. Experiments in cells have shown that hspB1 has chaperone activity, a cytoprotective role, regulates inflammatory gene expression, and drives cell proliferation. To investigate the function of the protein in vivo we generated hspB1-deficient mice. HspB1-deficient fibroblasts display increased expression of the pro-inflammatory cytokine, interleukin-6, compared to wild-type cells, but reduced proliferation. HspB1-deficient fibroblasts exhibit reduced entry into S phase and increased expression of cyclin-dependent kinase inhibitors p27(kip1) and p21(waf1). The expression of hspB1 protein and mRNA is also controlled by the cell cycle. To investigate the physiological function of hspB1 in regulating inflammation and cell proliferation we used an excisional cutaneous wound healing model. There was a significant impairment in the rate of healing of wounds in hspB1-deficient mice, characterised by reduced re-epithelialisation and collagen deposition but also increased inflammation. HspB1 deficiency augments neutrophil infiltration in wounds, driven by increased chemokine (C-X-C motif) ligand 1 expression. This appears to be a general mechanism as similar results were obtained in the air-pouch and peritonitis models of acute inflammation.
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EphB receptors trigger Akt activation and suppress Fas receptor-induced apoptosis in malignant T lymphocytes.
J. Immunol.
PUBLISHED: 10-28-2011
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Treatment of hematopoietic malignancies often requires allogeneic bone marrow transplantation, and the subsequent graft-versus-leukemia response is crucial for the elimination of malignant cells. Cytotoxic T lymphocytes and NK cells responsible for the immunoelimination express Fas ligand and strongly rely on the induction of Fas receptor-mediated apoptosis for their action. Although cancer cells are removed successfully by graft-versus-leukemia reactions in myeloid malignancies, their efficiency is low in T cell leukemias. This may be partially because of the ability of malignant T cells to escape apoptosis. Our work shows that Eph family receptor EphB3 is consistently expressed by malignant T lymphocytes, most frequently in combination with EphB6, and that stimulation with their common ligands, ephrin-B1 and ephrin-B2, strongly suppresses Fas-induced apoptosis in these cells. This effect is associated with Akt activation and with the inhibition of the Fas receptor-initiated caspase proteolytic cascade. Akt proved to be crucial for the prosurvival response, because inhibition of Akt, but not of other molecules central to T cell biology, including Src kinases, MEK1 and MEK2, blocked the antiapoptotic effect. Overall, this demonstrates a new role for EphB receptors in the protection of malignant T cells from Fas-induced apoptosis through Akt engagement and prevention of caspase activation. Because Fas-triggered apoptosis is actively involved in the graft-versus-leukemia response and cytotoxic T cells express ephrin-Bs, our observations suggest that EphB receptors are likely to support immunoevasivenes of T cell malignancies and may represent promising targets for therapies, aiming to enhance immunoelimination of cancerous T cells.
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Prevalence of HIV type 1 antiretroviral drug resistance mutations in Vietnam: a multicenter study.
AIDS Res. Hum. Retroviruses
PUBLISHED: 03-31-2011
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The prevalence of HIV-1 drug resistance mutations (DRMs) was determined for a cross-section of individuals (n=8654) in five centers across Vietnam (Hanoi, Hai Phong, Da Nang, Khanh Hoa, and Can Tho) between 2008 and 2009. Following serological screening for HIV infection, HIV-1 viral load was determined, using an in-house real-time reverse transcriptase polymerase chain reaction (RT-PCR) assay. Samples with quantifiable viral loads [all either commercial sex workers (CSW) or intravenous drug users (IDU)] underwent DRM analysis. Sequences were obtained for 92 treatment-naive individuals, the majority of whom were infected with HIV-1 CRF01_AE (99%), with one instance of subtype A1 also detected. DRMs were detected in seven treatment-naive individuals (7.6%). The most common DRMs observed were M184V, V75A/M, M41L, and K65R (NRTI) and K103N, G190A, and Y181C (NNRTI). Overall, the data from this first multicenter survey of DRMs in Vietnam indicate that the problem of transmitted drug resistance is of major concern in the highest-risk groups of IDU and CSW.
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Molecular epidemiological evaluation of the recent resurgence in mumps virus infections in Ireland.
J. Clin. Microbiol.
PUBLISHED: 07-21-2010
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Mumps is a vaccine-preventable disease; however, outbreaks have been reported in a number of countries with childhood immunization programs, particularly among young adults at the tertiary stage of education. We have retrospectively investigated the epidemiological, virological, and serological factors associated with mumps cases identified in Ireland from 2004 to 2009. Genetic analysis of mumps virus strain variability demonstrated that a single genotype, genotype G, was circulating, and it was also detected in cerebrospinal fluid samples obtained from patients with meningitis. We observed that younger individuals were disproportionately affected with neurological sequelae following mumps virus infection, and the average age of patients with mumps virus RNA detected in cerebrospinal fluid was 19.25 years (median, 19 years; range, 14 to 24 years). Our analysis showed a 4-fold rise in mumps cases in 2008-2009 and an increased incidence in infection in those >or=30 years of age. Over a 6-year period (2004 to 2009), a total of 7,805 serum samples were investigated; of this number, 1,813 (23%) were positive for mumps virus-specific IgM. We observed a strong bias for acute mumps virus infection in males compared to females (P < 10(-32)) that was independent of vaccination status.
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MAPKAP kinase 2 blocks tristetraprolin-directed mRNA decay by inhibiting CAF1 deadenylase recruitment.
J. Biol. Chem.
PUBLISHED: 07-01-2010
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Tristetraprolin (TTP) directs its target AU-rich element (ARE)-containing mRNAs for degradation by promoting removal of the poly(A) tail. The p38 MAPK pathway regulates mRNA stability via the downstream kinase MAPK-activated protein kinase 2 (MAPKAP kinase 2 or MK2), which phosphorylates and prevents the mRNA-destabilizing function of TTP. We show that deadenylation of endogenous ARE-containing tumor necrosis factor mRNA is inhibited by p38 MAPK. To investigate whether phosphorylation of TTP by MK2 regulates TTP-directed deadenylation of ARE-containing mRNAs, we used a cell-free assay that reconstitutes the mechanism in vitro. We find that phosphorylation of Ser-52 and Ser-178 of TTP by MK2 results in inhibition of TTP-directed deadenylation of ARE-containing RNA. The use of 14-3-3 protein antagonists showed that regulation of TTP-directed deadenylation by MK2 is independent of 14-3-3 binding to TTP. To investigate the mechanism whereby TTP promotes deadenylation, it was necessary to identify the deadenylases involved. The carbon catabolite repressor protein (CCR)4.CCR4-associated factor (CAF)1 complex was identified as the major source of deadenylase activity in HeLa cells responsible for TTP-directed deadenylation. CAF1a and CAF1b were found to interact with TTP in an RNA-independent fashion. We find that MK2 phosphorylation reduces the ability of TTP to promote deadenylation by inhibiting the recruitment of CAF1 deadenylase in a mechanism that does not involve sequestration of TTP by 14-3-3. Cyclooxygenase-2 mRNA stability is increased in CAF1-depleted cells in which it is no longer p38 MAPK/MK2-regulated.
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Cytokine and growth factor expression by HTLV-1 Lck-tax transgenic cells in SCID mice.
AIDS Res. Hum. Retroviruses
PUBLISHED: 05-05-2010
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The Tax protein encoded by HTLV-1 plays a key role in the development of ATL in infected individuals. Our previous studies showed that tax transgenic mice develop disease that is almost identical to human ATL, with widespread organ invasion by lymphomatous cells and the development of leukemia. The same pathology develops rapidly in SCID mice engrafted with cells from the transgenic animals. In the present study, we used this SCID model to analyze the expression levels of several cytokines, growth factors, and adhesion molecules to determine their possible involvement in the development of disease. We showed that Tax expression was undetectable at the protein level in the tax-transformed cells used to inoculate the SCID mice and that these cells displayed constitutive NF-kappaB and Akt activity. We demonstrated significant differences in the levels of circulating PDGF-BB, TNF-alpha, sICAM-1, and sVCAM-1 in inoculated animals. Cell-surface staining of the tax transgenic cells showed that they do not express receptors for any of the upregulated growth factors. Significant differences were not found in the secreted levels of bFGF, MMP9, VEGF, or E-selectin, whereas IL-2, IL-15, IL-6, IL-1beta, and IFN-gamma expression was undetectable. Even though the number of factors analyzed is limited, our study identified TNF-alpha, PDGF-BB, and the adhesion molecules sICAM-1 and sVCAM-1 as factors that may contribute to the high levels of organ infiltration by leukemic cells in this tax transgenic SCID model.
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Tax 1-independent induction of vascular endothelial growth factor in adult T-cell leukemia caused by human T-cell leukemia virus type 1.
J. Virol.
PUBLISHED: 03-17-2010
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Adult T-cell leukemia (ATL) is caused by human T-cell leukemia virus type 1 (HTLV-1). Elevated expression of vascular endothelial growth factor (VEGF) in ATL patients is associated with leukemic cell invasion and infiltration in different organs. The regulatory protein Tax 1 encoded by HTLV-1 plays a pivotal role in T-cell transformation by deregulating the function and expression of several cellular factors. In the present study, we examined the effect of Tax 1 on VEGF expression at transcriptional and posttranscriptional levels in order to elucidate the regulatory mechanisms involved. Using functional assays, we demonstrate that Tax 1 downregulates the VEGF promoter through a cluster of Sp1 sites located close to the transcriptional start site. Using gel mobility shift assays, we show that Tax 1 reduced Sp1:DNA complex formation. We demonstrate that the level of secreted VEGF was significantly lower in Tax 1-transfected 293T cells compared to nontransfected cells, which is consistent with the observed downregulatory effect of Tax 1 at the transcription level. We showed that VEGF was secreted by HTLV-1-transformed and nontransformed cells, irrespective of Tax 1 expression. Overall our data indicate that, contrary to a previous report, Tax 1 downregulates VEGF expression and suggest there are Tax 1-independent mechanisms of VEGF activation in ATL.
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High frequencies of functionally competent circulating Tax-specific CD8+ T cells in human T lymphotropic virus type 2 infection.
J. Immunol.
PUBLISHED: 08-05-2009
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Human T lymphotropic virus type 2 (HTLV-2) is characterized by a clinically asymptomatic persistent infection in the vast majority of infected individuals. In this study, we have characterized for the first time ex vivo specific CTL responses against the HTLV-2 Tax protein. We could detect CTL responses only against a single HLA-A*0201-restricted Tax2 epitope, comprising residues 11-19 (LLYGYPVYV), among three alleles screened. Virus-specific CTLs could be detected in most evaluated subjects, with frequencies as high as 24% of circulating CD8(+) T cells. The frequency of specific CTLs had a statistically significant positive correlation with proviral load levels. The majority of virus-specific CD8(+) T cells exhibited an effector memory/terminally differentiated phenotype, expressed high levels of cytotoxicity mediators, including perforin and granzyme B, and lysed in vitro target cells pulsed with Tax2((11-19)) synthetic peptide in a dose-dependent manner. Our findings suggest that a strong, effective CTL response may control HTLV-2 viral burden and that this may be a significant factor in maintaining persistent infection and in the prevention of disease in infected individuals.
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Post-transcriptional gene regulation by MAP kinases via AU-rich elements.
Front Biosci (Landmark Ed)
PUBLISHED: 03-11-2009
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Eukaryotic cells must continuously sense their environments, for example their attachment to extracellular matrix and proximity to other cells, differences in temperature or redox conditions, the presence of nutrients, growth factors, hormones, cytokines or pathogens. The information must then be integrated and an appropriate response initiated by modulating the cellular programme of gene expression. The mitogen-activated protein kinase (MAPK) signaling pathways play a critical role in this process. Decades of research have illuminated the many ways in which MAPKs regulate the synthesis of mRNA (transcription) via phosphorylation of transcription factors, cofactors, and other proteins. In recent years it has become increasingly clear that the control of mRNA destruction is equally important for cellular responses to extracellular cues, and is equally subject to regulation by MAPKs. This review will summarize our current understanding of post-transcriptional regulation of gene expression by the MAPKs and the proteins that are involved in this process.
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Expression profile and differential regulation of the Human I-mfa domain-Containing protein (HIC) gene in immune cells.
Immunol. Lett.
PUBLISHED: 03-05-2009
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The Human I-mfa domain-Containing protein, HIC, is a 246 amino acid protein that functions as a transcriptional regulator. Although the precise function of HIC remains to be clarified, the association of the HIC gene locus with myeloid neoplasms, its interactions with lymphotropic viruses such as EBV, HIV-1 and HTLV-1 and its expression in immune tissues suggest that HIC might have a modulatory role in immune cells. To further characterise the HIC functional relationship with the immune system, we sought to analyse the HIC gene expression profile in immune cells and to determine if immunomodulatory cytokines, such as interleukin (IL)-2, could regulate the expression of HIC mRNA. Relative quantitative real-time RT-PCR revealed that HIC mRNA is highly expressed in PBMCs and in various hematopoietic cell lines. The immunomodulatory cytokine IL-2 up-regulated HIC gene expression in PBMCs, CEM, MT-2 and U937 but markedly reduced HIC gene expression in Raji. Addition of cycloheximide indicated that the IL-2 effects were independent of de novo protein synthesis and that the HIC gene is a direct target of IL-2. Two cell lines (Jurkat and BJAB) displayed a distinct loss in HIC gene expression. However, when these cell lines were subjected to a combination of DNA methyltransferase and histone-deacetylase inhibitors, (5-aza-2-deoxycytidine and trichostatin A, respectively), HIC expression was de-repressed, indicating possible epigenetic control of HIC expression. Overall, our study describes that the immune expression of HIC is cell-specific, dynamic, and identifies the HIC gene as an IL-2 responsive gene. Furthermore, our de-repression studies support the hypothesis that HIC might represent a candidate tumor suppressor gene. Overall, this report provides new insights for a putative role of HIC in the modulation of immune and inflammatory responses and/or hematological malignancies.
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Phenotypic characterization of lymphocytes in HCV/HIV co-infected patients.
Viral Immunol.
PUBLISHED: 02-13-2009
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While hepatitis C virus (HCV)-specific immune responses are attenuated in HCV/HIV co-infected patients compared to those infected with HCV alone, the reasons for this remain unclear. In this study, the proportions of regulatory, naïve, and memory T cells, along with chemokine receptor expression, were measured in co-infected and mono-infected patients to determine if there is an alteration in the phenotypic profile of lymphocytes in these patients. HCV/HIV co-infected patients had increased proportions of CD4(+) naïve cells and decreased proportions of CD4(+) effector cells when compared to HCV mono-infected patients. The proportions of CD4(+) Tregs and CD4(+) CXCR3(+) T cells were also significantly lower in co-infected patients. A decrease in CD4(+) Tregs and subsequent loss of immunosuppressive function may contribute to the accelerated progression to liver disease in co-infected individuals. Dysregulation of immune responses following reduction in the proportions of CD4(+) CXCR3(+) Th-1 cells may contribute to the reduced functional capacity of HCV-specific immune responses in co-infected patients. The findings of this study provide new information on the T-cell immunophenotype in HCV/HIV co-infected patients when compared to those infected with HCV alone, and may provide insight into why cell-mediated immune responses are diminished during HCV infection.
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The p38 MAPK pathway inhibits tristetraprolin-directed decay of interleukin-10 and pro-inflammatory mediator mRNAs in murine macrophages.
FEBS Lett.
PUBLISHED: 02-12-2009
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p38 mitogen-activated protein kinase (MAPK) stabilises pro-inflammatory mediator mRNAs by inhibiting AU-rich element (ARE)-mediated decay. We show that in bone-marrow derived murine macrophages tristetraprolin (TTP) is necessary for the p38 MAPK-sensitive decay of several pro-inflammatory mRNAs, including cyclooxygenase-2 and the novel targets interleukin (IL)-6, and IL-1alpha. TTP(-/-) macrophages also strongly overexpress IL-10, an anti-inflammatory cytokine that constrains the production of the IL-6 despite its disregulation at the post-transcriptional level. TTP directly controls IL-10 mRNA stability, which is increased and insensitive to inhibition of p38 MAPK in TTP(-/-) macrophages. Furthermore, TTP enhances deadenylation of an IL-10 3-untranslated region RNA in vitro.
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Impact of fundoplication versus gastrojejunal feeding tubes on mortality and in preventing aspiration pneumonia in young children with neurologic impairment who have gastroesophageal reflux disease.
Pediatrics
PUBLISHED: 01-02-2009
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Aspiration pneumonia is the most common cause of death in children with neurologic impairment who have gastroesophageal reflux disease. Fundoplications and gastrojejunal feeding tubes are frequently employed to prevent aspiration pneumonia in this population. Which of these approaches is more effective in preventing aspiration pneumonia and/or improving survival is unknown. The objective of this study was to compare outcomes for children with neurologic impairment and gastroesophageal reflux disease after either a first fundoplication or a first gastrojejunal feeding tube.
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The p38 MAPK Pathway in Rheumatoid Arthritis: A Sideways Look.
Open Rheumatol J
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The p38 mitogen-activated protein kinase (MAPK) signaling pathway has been strongly implicated in many of the processes that underlie the pathology of rheumatoid arthritis (RA). For many years it has been considered a promising target for development of new anti-inflammatory drugs with which to treat RA and other chronic immune-mediated inflammatory diseases. However, several recent clinical trials have concluded in a disappointing manner. Why is this so, if p38 MAPK clearly contributes to the excessive production of inflammatory mediators, the destruction of bone and cartilage? We argue that, to explain the apparent failure of p38 inhibitors in the rheumatology clinic, we need to understand better the complexities of the p38 pathway and its many levels of communication with other cellular signaling pathways. In this review we look at the p38 MAPK pathway from a slightly different perspective, emphasising its role in post-transcriptional rather than transcriptional control of gene expression, and its contribution to the off-phase rather than the on-phase of the inflammatory response.
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Hepatitis C virus in Vietnam: high prevalence of infection in dialysis and multi-transfused patients involving diverse and novel virus variants.
PLoS ONE
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Hepatitis C virus (HCV) is a genetically diverse pathogen infecting approximately 2-3% of the worlds population. Herein, we describe results of a large, multicentre serological and molecular epidemiological study cataloguing the prevalence and genetic diversity of HCV in five regions of Vietnam; Ha Noi, Hai Phong, Da Nang, Khanh Hoa and Can Tho. Individuals (n=8654) with varying risk factors for infection were analysed for the presence of HCV Ab/Ag and, in a subset of positive specimens, for HCV RNA levels (n=475) and genotype (n=282). In lower risk individuals, including voluntary blood donors, military recruits and pregnant women, the prevalence of infection was 0.5% (n=26/5250). Prevalence rates were significantly higher (p<0.001) in intravenous drug users (IDUs; 55.6%, n=556/1000), dialysis patients (26.6%, n=153/575) commercial sex workers (CSWs; 8.7%, n=87/1000), and recipients of multiple blood transfusions (6.0%, n=32/529). The prevalence of HCV in dialysis patients varied but remained high in all regions (11-43%) and was associated with the receipt of blood transfusions [OR: 2.08 (1.85-2.34), p=0.001], time from first transfusion [OR: 1.07 (1.01-1.13), p=0.023], duration of dialysis [OR: 1.31 (1.19-1.43), p<0.001] and male gender [OR: 1.60 (1.06-2.41), p=0.026]. Phylogenetic analysis revealed high genetic diversity, particularly amongst dialysis and multi-transfused patients, identifying subtypes 1a (33%), 1b (27%), 2a (0.4%), 3a (0.7%), 3b (1.1%), 6a (18.8%), 6e (6.0%), 6h (4.6%), 6l (6.4%) and 2 clusters of novel genotype 6 variants (2.1%). HCV genotype 1 predominated in Vietnam (60%, n=169/282) but the proportion of infections attributable to genotype 1 varied between regions and risk groups and, in the Southern part of Vietnam, genotype 6 viruses dominated in dialysis and multi-transfused patients (73.9%). This study confirms a high prevalence of HCV infection in Vietnamese IDUs and, notably, reveals high levels of HCV infection associated with dialysis and blood transfusion.
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A multicentre molecular analysis of hepatitis B and blood-borne virus coinfections in Viet Nam.
PLoS ONE
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Hepatitis B (HBV) infection is endemic in Viet Nam, with up to 8.4 million individuals estimated to be chronically infected. We describe results of a large, multicentre seroepidemiological and molecular study of the prevalence of HBV infection and blood-borne viral coinfections in Viet Nam. Individuals with varying risk factors for infection (n = 8654) were recruited from five centres; Ha Noi, Hai Phong, Da Nang, Khanh Hoa and Can Tho. A mean prevalence rate of 10.7% was observed and levels of HBsAg were significantly higher in injecting drug users (IDUs) (17.4%, n = 174/1000) and dialysis patients (14.3%, n = 82/575) than in lower-risk groups (9.4%; p<0.001). Coinfection with HIV was seen in 28% of HBV-infected IDUs (n = 49/174) and 15.2% of commercial sex workers (CSWs; n = 15/99). HCV infection was present in 89.8% of the HBV-HIV coinfected IDUs (n = 44/49) and 40% of HBV-HIV coinfected CSWs (n = 16/40). Anti-HDV was detected in 10.7% (n = 34/318) of HBsAg positive individuals. Phylogenetic analysis of HBV S gene (n = 187) showed a predominance of genotype B4 (82.6%); genotypes C1 (14.6%), B2 (2.7%) and C5 (0.5%) were also identified. The precore mutation G1896A was identified in 35% of all specimens, and was more frequently observed in genotype B (41%) than genotype C (3%; p<0.0001). In the immunodominant a region of the surface gene, point mutations were identified in 31% (n = 58/187) of sequences, and 2.2% (n = 4/187) and 5.3% (n = 10/187) specimens contained the major vaccine escape mutations G145A/R and P120L/Q/S/T, respectively. 368 HBsAg positive individuals were genotyped for the IL28B SNP rs12979860 and no significant association between the IL28B SNP and clearance of HBsAg, HBV viral load or HBeAg was observed. This study confirms the high prevalence of HBV infection in Viet Nam and also highlights the significant levels of blood-borne virus coinfections, which have important implications for hepatitis-related morbidity and development of effective management strategies.
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Risk of gastrointestinal illness associated with the consumption of rainwater: a systematic review.
Environ. Sci. Technol.
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The collection of rainwater for human consumption is a practice well established in many parts of the world. Much of the research to date regarding this inexpensive and sustainable source has focused on its microbiological or chemical quality and there have been no reviews of epidemiological evidence regarding actual health risks associated with rainwater consumption. Electronic bibliographic databases were searched for epidemiological studies that attempted to quantify the risk of gastrointestinal disease linked to the consumption of harvested rainwater. Online databases were searched from the oldest date up to January 2011. Both observational and experimental studies were included. In addition, reference sections of key articles were searched and authors of previous studies were contacted where appropriate. Studies were assessed for relevance independently and in duplicate. Searches returned a total of 764 articles, 13 met inclusion criteria, 5 of these were outbreak reports, and 9 were studies of other design types. Pooled subgroup analysis suggests that rainwater is associated with reduced risk of illness compared to unimproved supplies (relative risk 0.57 95% CI 0.42, 0.77). There was no significant difference in risk in the pooled analysis of studies that compared rainwater to improved water supplies (relative risk 0.82 95% CI 0.38, 1.73). However, there was heterogeneity with one study showing an excess risk of campylobacteriosis. Classification of outbreak reports determined that 4 reports were "strongly associated with rainwater" while 1 report was "probably associated with rainwater". We conclude that the evidence suggests that rainwater is safer than water from unimproved water supplies. Where feasible rainwater harvesting should be encouraged as a step toward achieving millennium development targets.
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Seroepidemiology of the recent mumps virus outbreaks in Ireland.
J. Clin. Virol.
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Two recent mumps outbreaks have occurred in Ireland in 2004/2005 and 2008/2009.
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HIV type 1 coreceptor tropism, CCR5 genotype, and integrase inhibitor resistance profiles in Vietnam: implications for the introduction of new antiretroviral regimens.
AIDS Res. Hum. Retroviruses
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In Vietnam, where an estimated 280,000 people will be HIV-positive by 2012, recommended antiretroviral regimens do not include more recently developed therapeutics, such as Integrase inhibitors (INI) and coreceptor antagonists. This study examined HIV-1 coreceptor tropism and INI drug resistance profiles, in parallel with CCR5 genotypes, in a cohort of 60 HIV-positive individuals from different regions of Vietnam. No evidence of INI resistance was detected. Some 40% of individuals had X4-tropic HIV-1, making them unsuitable for treatment with CCR5 antagonists. We identified a novel CCR5 variant-S272P-along with other, previously reported variants: G106R, C178R, W153C, R223Q, and S336I. Interestingly, CCR5 variants known to affect HIV-1 infectivity were observed only in individuals harboring X4-tropic virus. Together, this study presents valuable baseline information on HIV-1 INI resistance, coreceptor tropism, and CCR5 variants in HIV-positive individuals in Vietnam. This should help inform policy on the future use of novel antiretrovirals in Vietnam.
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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

How does it work?

We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

Video X seems to be unrelated to Abstract Y...

In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.