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Sample records for monocyte-derived hepatocyte-stimulating factor

  1. Effect of hepatocyte-stimulating factor and glucocorticoids on plasma fibronectin levels.

    PubMed Central

    Amrani, D L; Mauzy-Melitz, D; Mosesson, M W

    1986-01-01

    We evaluated the effects of hepatocyte-stimulating factor (HSF) and a glucocorticoid (dexamethasone) on changes in the levels, in vivo and in vitro, of plasma fibronectin (Fn), a glycoprotein that is synthesized and secreted by hepatocytes. In turpentine-treated chickens, plasma levels of Fn, which peaked at 48 h (whereas fibrinogen levels were maximum at 72 h) rose 200-250% over basal levels, whereas albumin levels decreased by 20-40%. Corticosterone levels in serum samples taken between 5 and 48 h after injection revealed a 124% increase in hormone levels at 24 h in turpentine-treated chickens. We also showed that circulating HSF levels were maximal 8 to 12 h after injection and that HSF activity, as assessed by molecular-exclusion chromatography, was eluted in the 30-45 kDa range. Addition of either serum-derived HSF or dexamethasone (2 nM) to chick hepatocyte cultures resulted in a 130-150% increase in secreted Fn as well as in fibrinogen. When HSF and dexamethasone were added together, a 360-489% increase in the secreted levels of both proteins was found. Chicken mononuclear phagocytic cells treated with lipopolysaccharide secreted an HSF activity that was eluted in two peaks, a minor peak at approximately 70 kDa and a major peak in the 25-40 kDa range. Addition of mononuclear-cell-derived HSF resulted in a greater increase in Fn levels than did the addition of serum HSF. These findings indicate that Fn, like fibrinogen, is an acute-phase protein, the production of which, at least in chickens, is stimulated by HSF and glucocorticoids in an additive manner. PMID:3099768

  2. Uptake of exogenous free cholesterol induces upregulation of tissue factor expression in human monocyte-derived macrophages.

    PubMed Central

    Lesnik, P; Rouis, M; Skarlatos, S; Kruth, H S; Chapman, M J

    1992-01-01

    Lipid-laden macrophages present as foam cells may contribute to the hyperthrombotic state of human atherosclerotic lesions by the production of tissue factor (TF). We investigated the effect of exogenous nonlipoprotein cholesterol on the expression of TF by human monocyte-derived macrophages in culture. Nonlipoprotein cholesterol at 50 micrograms/ml increased TF activity 4-fold; TF induction was dose- and time-dependent. Expression of TF activity was positively correlated with the free cholesterol content of monocyte-derived macrophages, was increased upon inhibition of cholesterol esterification, and reflected de novo synthesis of TF protein. TF expression in cholesterol-loaded macrophages remained sensitive to stimulation (approximately 12-fold) by bacterial lipopolysaccharide, indicating that intracellular free cholesterol and lipopolysaccharide act by distinct mechanisms in inducing TF procoagulant activity. Our results suggest that loading human monocyte-derived macrophages with free cholesterol induces upregulation of TF expression, thereby contributing to thrombus formation at sites of plaque rupture. Images PMID:1438222

  3. Characterization of a receptor for human monocyte-derived neutrophil chemotactic factor/interleukin-8

    SciTech Connect

    Grob, P.M.; David, E.; Warren, T.C.; DeLeon, R.P.; Farina, P.R.; Homon, C.A. )

    1990-05-15

    Monocyte-derived neutrophil chemotactic factor/interleukin-8 (MDNCF/IL-8) is an 8,000-dalton protein produced by monocytes which exhibits activity as a chemoattractant for neutrophils with maximal activity achieved at a concentration of 50 ng/ml. This polypeptide has been iodinated by chloramine-T methodology (350 Ci/mM), and specific receptors for MDNCF/IL-8 have been detected on human neutrophils, U937 cells, THP-1 cells, and dimethyl sulfoxide-differentiated HL-60 cells. The binding of MDNCF/IL-8 to human neutrophils is not inhibited by interleukin-1 alpha, tumor necrosis factor-alpha, insulin, or epidermal growth factor. In addition, chemoattractants such as C5a, fMet-Leu-Phe, leukotriene B4, and platelet-activating factor fail to inhibit binding, suggesting that MDNCF/IL-8 utilizes a unique receptor. The receptor for MDNCF/IL-8 is apparently glycosylated since ligand binding is inhibited by the presence of wheat germ agglutinin, a lectin with a binding specificity for N-acetylglucosamine and neuraminic acid. Steady state binding experiments indicate Kd values of 4 and 0.5 nM and receptor numbers of 75,000 and 7,400 for human neutrophils and differentiated HL-60 cells, respectively. 125I-MDNCF/IL-8 bound to human neutrophils is rapidly internalized and subsequently released from cells as trichloroacetic acid-soluble radioactivity. Affinity labeling experiments suggest that the human neutrophil MDNCF/IL-8 receptor exhibits a mass of approximately 58,000 daltons.

  4. The Complement Inhibitor Factor H Generates an Anti-Inflammatory and Tolerogenic State in Monocyte-Derived Dendritic Cells.

    PubMed

    Olivar, Rut; Luque, Ana; Cárdenas-Brito, Sonia; Naranjo-Gómez, Mar; Blom, Anna M; Borràs, Francesc E; Rodriguez de Córdoba, Santiago; Zipfel, Peter F; Aran, Josep M

    2016-05-15

    The activation of the complement system is a key initiating step in the protective innate immune-inflammatory response against injury, although it may also cause harm if left unchecked. The structurally related soluble complement inhibitors C4b-binding protein (C4BP) and factor H (FH) exert a tight regulation of the classical/lectin and alternative pathways of complement activation, respectively, attenuating the activity of the C3/C5 convertases and, consequently, avoiding serious damage to host tissues. We recently reported that the acute-phase C4BP isoform C4BP lacking the β-chain plays a pivotal role in the modulation of the adaptive immune responses. In this study, we demonstrate that FH acts in the early stages of monocyte to dendritic cell (DC) differentiation and is able to promote a distinctive tolerogenic and anti-inflammatory profile on monocyte-derived DCs (MoDCs) challenged by a proinflammatory stimulus. Accordingly, FH-treated and LPS-matured MoDCs are characterized by altered cytoarchitecture, resembling immature MoDCs, lower expression of the maturation marker CD83 and the costimulatory molecules CD40, CD80, and CD86, decreased production of key proinflammatory Th1-cytokines (IL-12, TNF-α, IFN-γ, IL-6, and IL-8), and preferential production of immunomodulatory mediators (IL-10 and TGF-β). Moreover, FH-treated MoDCs show low Ag uptake and, when challenged with LPS, display reduced CCR7 expression and chemotactic migration, impaired CD4(+) T cell alloproliferation, inhibition of IFN-γ secretion by the allostimulated T cells, and, conversely, induction of CD4(+)CD127(low/negative)CD25(high)Foxp3(+) regulatory T cells. Thus, this novel noncanonical role of FH as an immunological brake able to directly affect the function of MoDCs in an inflammatory environment may exhibit therapeutic potential in hypersensitivity, transplantation, and autoimmunity. PMID:27076676

  5. Differential expression of HIV-1 interfering factors in monocyte-derived macrophages stimulated with polarizing cytokines or interferons

    NASA Astrophysics Data System (ADS)

    Jiménez, Viviana Cobos; Booiman, Thijs; de Taeye, Steven W.; van Dort, Karel A.; Rits, Maarten A. N.; Hamann, Jörg; Kootstra, Neeltje A.

    2012-10-01

    HIV-1 replication in macrophages can be regulated by cytokines and infection is restricted in macrophages activated by type I interferons and polarizing cytokines. Here, we observed that the expression levels of the cellular factors Trim5α, CypA, APOBEC3G, SAMHD-1, Trim22, tetherin and TREX-1, and the anti-HIV miRNAs miR-28, miR-150, miR-223 and miR-382 was upregulated by IFN-α and IFN-β in macrophages, which may account for the inhibiting effect on viral replication and the antiviral state of these cells. Expression of these factors was also increased by IFN-γ +/- TNF-α, albeit to a lesser extent; yet, HIV-1 replication in these cells was not restricted at the level of proviral synthesis, indicating that these cellular factors only partially contribute to the observed restriction. IL-4, IL-10 or IL-32 polarization did not affect the expression of cellular factors and miRNAs, suggesting only a limited role for these cellular factors in restricting HIV-1 replication in macrophages.

  6. Identification and characterization of a monocyte-derived neutrophil-activating factor in corticosteroid-resistant bronchial asthma.

    PubMed Central

    Wilkinson, J R; Crea, A E; Clark, T J; Lee, T H

    1989-01-01

    Peripheral blood mononuclear cells (PBMC) were isolated from seven normal subjects, eight asthmatic subjects clinically sensitive to corticosteroids (CS), and eight asthmatic subjects clinically resistant to corticosteroids (CR). PBMC were cultured at 37 degrees C for 24 h in the absence or presence of 10(-16) to 10(-4) M hydrocortisone. Calcium ionophore (A23187)-activated neutrophils (PMN) primed by supernatants of PBMC from asthmatic subjects cultured in the absence of hydrocortisone generated approximately threefold more leukotriene B4 than PMN primed by supernatants of PBMC from normal subjects (P less than 0.05). Incubation of PBMC derived from CS subjects with 10(-8) M hydrocortisone completely inhibited the production of the enhancing activity (P less than 0.01), whereas in CR subjects hydrocortisone at concentrations up to 10(-4) M did not suppress the release of enhancing activity. The enhancing activity was produced by monocytes. Enhancing activity eluted with an Mr of 3,000 D and a pI of 7.1. It eluted at 10% acetonitrile after reverse-phase HPLC. The activity was destroyed by heating to 60 degrees C for 60 min and was sensitive to pronase treatment. The purified factor also enhanced superoxide generation by PMN which had been stimulated submaximally by phorbol myristate acetate. Images PMID:2556450

  7. The Anti-Apoptotic Effect of Respiratory Syncytial Virus on Human Peripheral Blood Neutrophils is Mediated by a Monocyte Derived Soluble Factor

    PubMed Central

    Coleman, Christopher M; Plant, Karen; Newton, Susan; Hobson, Lynsey; Whyte, Moira K.B; Everard, Mark L

    2011-01-01

    Respiratory Syncytial Virus (RSV) causes annual epidemics of respiratory disease particularly affecting infants. The associated airway inflammation is characterized by an intense neutrophilia. This neutrophilic inflammation appears to be responsible for much of the pathology and symptoms. Previous work from our group had shown that there are factors within the airways of infants with RSV bronchiolitis that inhibit neutrophil apoptosis. This study was undertaken to determine if RSV can directly affect neutrophil survival. Neutrophils were isolated from citrated venous blood (collected from healthy adult volunteers) by discontinuous plasma: Percoll gradient centrifugation and, in some experiments, further purified by negative immunomagnetic bead selection. The effect of RSV on neutrophil survival was measured by Annexin V-PE /To-Pro-3 staining and by morphological changes, using Dif-Quick staining of cytospins. Inhibition of neutrophil apoptosis was observed in neutrophils isolated by standard plasma:Percoll gradient when exposed to RSV but not in ultra pure neutrophil preparations. Adding monocytes back to ultra purified preparations restored the effect. The inhibition of apoptosis was observed with both active and UV inactivated virus. The effect is dependent on a soluble factor and appears to be dependent on CD14 receptors on the monocytes. PMID:22046209

  8. Changes in the proteomic profile during differentiation and maturation of human monocyte-derived dendritic cells stimulated with granulocyte macrophage colony stimulating factor/interleukin-4 and lipopolysaccharide.

    PubMed

    Pereira, Sandra Rodrigues; Faça, Vitor Marcel; Gomes, Glauce Gaspar; Chammas, Roger; Fontes, Aparecida Maria; Covas, Dimas Tadeu; Greene, Lewis Joel

    2005-04-01

    Dendritic cells (DCs) are highly specialized antigen-presenting cells that play an essential role in the immune response. We used the proteomic approach based on two-dimensional gel electrophoresis and mass spectrometry to identify the protein changes that occur during differentiation of DCs from monocytes (Mo) stimulated with granulocyte macrophage colony stimulating factor/interleukin-4 (GM-CSF/IL-4) and during the maturation of immature DCs stimulated with lipopolysaccharide. Sixty-three differentially expressed proteins (+/- two-fold) were unambiguously identified with sequence coverage greater than 20%. They corresponded to only 36 different proteins, because 11 were present as 38 electrophoretic forms. Some proteins such as tropomyosin 4 and heat shock protein 71 presented differentially expressed electrophoretic forms, suggesting that many of the changes in protein expression that accompany differentiation and maturation of DCs occur in post-translationally modified proteins. The largest differences in expression were observed for actin (21-fold in Mo), Rho GDP-dissociation inhibitor 2 (20-fold in Mo), vimentin (eight-fold in immature DCs), lymphocyte-specific protein 1 (12-fold in mature DCs) and thioredoxin (14-fold in mature DCs). Several proteins are directly related to functional and morphological characteristics of DCs, such as cytoskeletal proteins (cytoskeleton rearrangement) and chaperones (antigen processing and presentation), but other proteins have not been assigned specific functions in DCs. Only a few proteins identified here were the same as those reported in proteomic studies of DCs, which used different stimuli to produce the cells (GM-CSF/IL-4 and tumor necrosis factor-alpha). These data suggest that the DC protein profile depends on the stimuli used for differentiation and especially for maturation. PMID:15800872

  9. Early exposure of interferon-γ inhibits signal transducer and activator of transcription-6 signalling and nuclear factor κB activation in a short-term monocyte-derived dendritic cell culture promoting ‘FAST’ regulatory dendritic cells

    PubMed Central

    Rojas-Canales, D; Krishnan, R; Jessup, C F; Coates, P T

    2012-01-01

    Interferon (IFN)-γ is a cytokine with immunomodulatory properties, which has been shown previously to enhance the generation of tolerogenic dendritic cells (DC) when administered early ex vivo in 7-day monocyte-derived DC culture. To generate tolerogenic DC rapidly within 48 h, human monocytes were cultured for 24 h with interleukin (IL)-4 and granulocyte–macrophage colony-stimulating factor (GM-CSF) in the presence (IFN-γ-DC) or absence of IFN-γ (500 U/ml) (UT-DC). DC were matured for 24 h with TNF-α and prostaglandin E2 (PGE2). DC phenotype, signal transducer and activator of transcription-6 (STAT-6) phosphorylation and promotion of CD4+CD25+CD127neg/lowforkhead box P3 (FoxP3)hi T cells were analysed by flow cytometry. DC nuclear factor (NF)-κB transcription factor reticuloendotheliosis viral oncogene homologue B (RELB) and IL-12p70 protein expression were also determined. Phenotypically, IFN-γ-DC displayed reduced DC maturation marker CD83 by 62% and co-stimulation molecules CD80 (26%) and CD86 (8%). IFN-γ treatment of monocytes inhibited intracellular STAT6, RELB nuclear translocation and IL-12p70 production. IFN-γ-DC increased the proportion of CD4+CD25+CD127neg/lowfoxp3hi T cells compared to UT-DC from 12 to 23%. IFN-γ-DC primed T cells inhibited antigen-specific, autologous naive T cell proliferation by 70% at a 1:1 naive T cells to IFN-γ-DC primed T cell ratio in suppression assays. In addition, we examined the reported paradoxical proinflammatory effects of IFN-γ and confirmed in this system that late IFN-γ exposure does not inhibit DC maturation marker expression. Early IFN-γ exposure is critical in promoting the generation of regulatory DC. Early IFN-γ modulated DC generated in 48 h are maturation arrested and promote the generation of antigen-specific regulatory T cells, which may be clinically applicable as a novel cellular therapy for allograft rejection. PMID:22288588

  10. Role of neoplastic monocyte-derived fibrocytes in primary myelofibrosis.

    PubMed

    Verstovsek, Srdan; Manshouri, Taghi; Pilling, Darrell; Bueso-Ramos, Carlos E; Newberry, Kate J; Prijic, Sanja; Knez, Liza; Bozinovic, Ksenija; Harris, David M; Spaeth, Erika L; Post, Sean M; Multani, Asha S; Rampal, Raajit K; Ahn, Jihae; Levine, Ross L; Creighton, Chad J; Kantarjian, Hagop M; Estrov, Zeev

    2016-08-22

    Primary myelofibrosis (PMF) is a fatal neoplastic disease characterized by clonal myeloproliferation and progressive bone marrow (BM) fibrosis thought to be induced by mesenchymal stromal cells stimulated by overproduced growth factors. However, tissue fibrosis in other diseases is associated with monocyte-derived fibrocytes. Therefore, we sought to determine whether fibrocytes play a role in the induction of BM fibrosis in PMF. In this study, we show that BM from patients with PMF harbors an abundance of clonal, neoplastic collagen- and fibronectin-producing fibrocytes. Immunodeficient mice transplanted with myelofibrosis patients' BM cells developed a lethal myelofibrosis-like phenotype. Treatment of the xenograft mice with the fibrocyte inhibitor serum amyloid P (SAP; pentraxin-2) significantly prolonged survival and slowed the development of BM fibrosis. Collectively, our data suggest that neoplastic fibrocytes contribute to the induction of BM fibrosis in PMF, and inhibiting fibrocyte differentiation with SAP may interfere with this process. PMID:27481130

  11. Inhibition of the Differentiation of Monocyte-Derived Dendritic Cells by Human Gingival Fibroblasts

    PubMed Central

    Séguier, Sylvie; Tartour, Eric; Guérin, Coralie; Couty, Ludovic; Lemitre, Mathilde; Lallement, Laetitia; Folliguet, Marysette; Naderi, Samah El; Terme, Magali; Badoual, Cécile; Lafont, Antoine; Coulomb, Bernard

    2013-01-01

    We investigated whether gingival fibroblasts (GFs) can modulate the differentiation and/or maturation of monocyte-derived dendritic cells (DCs) and analyzed soluble factors that may be involved in this immune modulation. Experiments were performed using human monocytes in co-culture with human GFs in Transwell® chambers or using monocyte cultures treated with conditioned media (CM) from GFs of four donors. The four CM and supernatants from cell culture were assayed by ELISA for cytokines involved in the differentiation of dendritic cells, such as IL-6, VEGF, TGFβ1, IL-13 and IL-10. The maturation of monocyte-derived DCs induced by LPS in presence of CM was also studied. Cell surface phenotype markers were analyzed by flow cytometry. In co-cultures, GFs inhibited the differentiation of monocyte-derived DCs and the strength of this blockade correlated with the GF/monocyte ratio. Conditioned media from GFs showed similar effects, suggesting the involvement of soluble factors produced by GFs. This inhibition was associated with a lower stimulatory activity in MLR of DCs generated with GFs or its CM. Neutralizing antibodies against IL-6 and VEGF significantly (P<0.05) inhibited the inhibitory effect of CM on the differentiation of monocytes-derived DCs and in a dose dependent manner. Our data suggest that IL-6 is the main factor responsible for the inhibition of DCs differentiation mediated by GFs but that VEGF is also involved and constitutes an additional mechanism. PMID:23936476

  12. Monocyte Heterogeneity: Consequences for Monocyte-Derived Immune Cells

    PubMed Central

    de Vries, Teun J.; Everts, Vincent

    2016-01-01

    Blood monocytes are precursors of dendritic cells, macrophages, and osteoclasts. They are a heterogeneous cell population with differences in size, phenotype, and function. Although monocytes maintain several tissue-specific populations of immune cells in homeostasis, their contribution to populations of dendritic cells, macrophages, and osteoclasts is significantly increased in inflammation. Identification of a growing number of functionally different subsets of cells within populations of monocyte-derived immune cells has recently put monocyte heterogeneity into sharp focus. Here, we summarize recent findings in monocyte heterogeneity and their differentiation into dendritic cells, macrophages, and osteoclasts. We also discuss these advances in the context of the formation of functionally different monocyte-derived subsets of dendritic cells, macrophages, and osteoclasts. PMID:27478854

  13. Antigen Presentation by Monocytes and Monocyte-derived Cells

    PubMed Central

    Randolph, Gwendalyn J.; Jakubzick, Claudia; Qu, Chunfeng

    2008-01-01

    Summary Monocytes are circulating mononuclear phagocytes with a fundamental capacity to differentiate into macrophages. This differentiation can, in the presence of the right environmental cues, be re-directed instead to dendritic cells (DCs). Recent advances have been made in understanding the role of monocytes and their derivatives in presenting antigen to drive immune responses, and we review this topic herein. We briefly discuss the heterogeneity of monocytes in the blood and subsequently raise the possibility that one of the major monocyte phenotypes in the blood corresponds with a population of “blood DCs” previously proposed to drive T-independent antibody reactions in the spleen. Then we evaluate the role of monocytes in T-dependent immunity, considering their role in acquiring antigens for presentation prior to exiting the bloodstream and their ability to differentiate into macrophages versus antigen-presenting DCs. Finally, we review recent literature on the role of monocyte-derived cells in cross-presentation and discuss the possibility that monocyte-derived cells participate critically in processing antigen for cross-priming, even if they do not present that antigen to T cells themselves. PMID:18160272

  14. Human Monocyte-Derived Osteoclasts Are Targeted by Staphylococcal Pore-Forming Toxins and Superantigens.

    PubMed

    Flammier, Sacha; Rasigade, Jean-Philippe; Badiou, Cédric; Henry, Thomas; Vandenesch, François; Laurent, Frédéric; Trouillet-Assant, Sophie

    2016-01-01

    Staphylococcus aureus is the leading cause of bone and joint infections (BJIs). Staphylococcal pathogenesis involves numerous virulence factors including secreted toxins such as pore-forming toxins (PFTs) and superantigens. The role of these toxins on BJI outcome is largely unknown. In particular, few studies have examined how osteoclasts, the bone-resorbing cells, respond to exposure to staphylococcal PFTs and superantigens. We investigated the direct impact of recombinant staphylococcal toxins on human primary mature monocyte-derived osteoclasts, in terms of cytotoxicity and cell activation with cell death and bone resorption assays, using macrophages of the corresponding donors as a reference. Monocyte-derived osteoclasts displayed similar toxin susceptibility profiles compared to macrophages. Specifically, we demonstrated that the Panton-Valentine leukocidin, known as one of the most powerful PFT which lyses myeloid cells after binding to the C5a receptor, was able to induce the death of osteoclasts. The archetypal superantigen TSST-1 was not cytotoxic but enhanced the bone resorption activity of osteoclasts, suggesting a novel mechanism by which superantigen-producing S. aureus can accelerate the destruction of bone tissue during BJI. Altogether, our data indicate that the diverse clinical presentations of BJIs could be related, at least partly, to the toxin profiles of S. aureus isolates involved in these severe infections. PMID:26934588

  15. Human Monocyte-Derived Osteoclasts Are Targeted by Staphylococcal Pore-Forming Toxins and Superantigens

    PubMed Central

    Flammier, Sacha; Rasigade, Jean-Philippe; Badiou, Cédric; Henry, Thomas; Vandenesch, François; Laurent, Frédéric; Trouillet-Assant, Sophie

    2016-01-01

    Staphylococcus aureus is the leading cause of bone and joint infections (BJIs). Staphylococcal pathogenesis involves numerous virulence factors including secreted toxins such as pore-forming toxins (PFTs) and superantigens. The role of these toxins on BJI outcome is largely unknown. In particular, few studies have examined how osteoclasts, the bone-resorbing cells, respond to exposure to staphylococcal PFTs and superantigens. We investigated the direct impact of recombinant staphylococcal toxins on human primary mature monocyte-derived osteoclasts, in terms of cytotoxicity and cell activation with cell death and bone resorption assays, using macrophages of the corresponding donors as a reference. Monocyte-derived osteoclasts displayed similar toxin susceptibility profiles compared to macrophages. Specifically, we demonstrated that the Panton-Valentine leukocidin, known as one of the most powerful PFT which lyses myeloid cells after binding to the C5a receptor, was able to induce the death of osteoclasts. The archetypal superantigen TSST-1 was not cytotoxic but enhanced the bone resorption activity of osteoclasts, suggesting a novel mechanism by which superantigen-producing S. aureus can accelerate the destruction of bone tissue during BJI. Altogether, our data indicate that the diverse clinical presentations of BJIs could be related, at least partly, to the toxin profiles of S. aureus isolates involved in these severe infections. PMID:26934588

  16. Effect of cytokines on Siglec-1 and HIV-1 entry in monocyte-derived macrophages: the importance of HIV-1 envelope V1V2 region.

    PubMed

    Jobe, Ousman; Trinh, Hung V; Kim, Jiae; Alsalmi, Wadad; Tovanabutra, Sodsai; Ehrenberg, Philip K; Peachman, Kristina K; Gao, Guofen; Thomas, Rasmi; Kim, Jerome H; Michael, Nelson L; Alving, Carl R; Rao, Venigalla B; Rao, Mangala

    2016-06-01

    Monocytes and monocyte-derived macrophages express relatively low levels of CD4. Despite this, macrophages can be effectively infected with human immunodeficiency virus type 1. Macrophages have a critical role in human immunodeficiency virus type 1 transmission; however, the mechanism or mechanisms of virus infection are poorly understood. We report that growth factors, such as granulocyte macrophage colony-stimulating factor and macrophage colony-stimulating factor affect the phenotypic profile and permissiveness of macrophages to human immunodeficiency virus type 1. Human immunodeficiency virus type 1 infection of monocyte-derived macrophages derived from granulocyte macrophage and macrophage colony-stimulating factors was predominantly facilitated by the sialic acid-binding immunoglobulin-like lectin-1. The number of sialic acid-binding immunoglobulin-like lectin receptors on macrophage colony-stimulating factor-derived monocyte-derived macrophages was significantly greater than on granulocyte macrophage colony-stimulating factor-derived monocyte-derived macrophages, and correspondingly, human immunodeficiency virus type 1 infection was greater in the macrophage colony-stimulating factor-derived monocyte-derived macrophages. Single-genome analysis and quantitative reverse transcriptase-polymerase chain reaction revealed that the differences in infectivity was not due to differences in viral fitness or in viral variants with differential infectivity but was due to reduced viral entry into the granulocyte macrophage colony-stimulating factor-derived monocyte-derived macrophages. Anti-sialic acid-binding immunoglobulin-like lectin, trimeric glycoprotein 145, and scaffolded V1V2 proteins were bound to sialic acid-binding immunoglobulin-like lectin and significantly reduced human immunodeficiency virus type 1 entry and infection. Furthermore, sialic acid residues present in the V1V2 region of the envelope protein mediated human immunodeficiency virus type 1

  17. Differential Responses Between Monocytes and Monocyte-Derived Macrophages for Lipopolysaccharide Stimulation of Calves

    PubMed Central

    Guo, Yijie; Zhao, Guoqi; Tanaka, Sachi; Yamaguchi, Takahiro

    2009-01-01

    In this experiment Toll-like receptor expression pattern in monocytes and monocyte-derived macrophages by lipopolysaccharide (LPS) stimulation was examined. Jugular venous blood was collected from four Japanese calves, and the peripheral blood mononuclear cells (PBMCs) were isolated. The cells were directly used for collecting monocytes by magnetic cell sorting or cultured for 7 days to collect monocyte-derived macrophages in Repcell. Then we analyzed the mRNA expression pattern of TLRs and cytokines in monocytes and monocyte-derived macrophages after LPS stimulation for 24 h. LPS stimulation of both monocytes and monocyte-derived macrophages resulted in an increase in the levels of mRNA transcripts for TNF-α, IL-6 and IL-8. Moreover, TNF-α and IL-6 mRNA expressions were significantly augmented by LPS stimulation in monocyte-derived macrophages. TLRs mRNA expressions were unchanged after LPS stimulation of monocytes, while TLRs mRNA expressions in monocyte-derived macrophages were complicated. TLR1, 3, 5, 8 and 10 were significantly decreased after LPS stimulation and there were no differences in the mRNA expressions of TLR2, 4, 6 and 7 between the groups of control and LPS stimulation. Besides, no expression of TLR9 was found. As antigen presenting cells, monocytes and monocyte-derived macrophages respond differently to LPS, so they may have different functions in the innate immune system. PMID:19567206

  18. Superinduction of interleukin 8 mRNA in activated monocyte derived macrophages from rheumatoid arthritis patients

    PubMed Central

    Rodenburg, R.; van den Hoogen, F. H J; Barrera, P.; van Venrooij, W. J; van de Putte, L. B A

    1999-01-01

    OBJECTIVE—Synovial inflammation in patients with rheumatoid arthritis (RA) is characterised by the presence of large numbers of highly activated monocytes and macrophages. The importance of these cells in the aethiopathogenesis and prognosis of RA is increasingly recognised. The object of this report is to determine whether monocytes and monocyte derived macrophages of RA patients produce increased cytokine mRNA levels.
METHODS—Monocyte derived macrophages from RA patients and healthy controls were cultured either in the absence or presence of lipopolysaccharide. The expression levels of the mRNAs encoding GAPDH, interleukin 1β (IL1β), IL8, and α2 macroglobulin in these cells were analysed by reverse transcriptase-polymerase chain reaction (RT-PCR).
RESULTS—Activated monocyte derived macrophages from RA patients produce significantly higher IL8 mRNA levels than activated macrophages from healthy controls. By contrast, resting RA and control macrophages produce similar levels of IL8 mRNA. Culturing of activated macrophages in the presence of RA or control sera has no effect on the expression levels of IL8 mRNA. No significant differences between RA and control macrophages were observed in the expression levels of IL1β and α2 macroglobulin mRNAs.
CONCLUSION—These data indicate that the increased IL8 mRNA production capacity of RA macrophages upon activation is an intrinsic property of these cells, and is not attributable to factors present in the circulation. Based on these observations, it is postulated that this innate hyper-responsiveness of RA macrophages contributes to the high IL8 levels present in the synovial fluid of rheumatoid joints, and is implicated in the chemotactic gradient leading to the homing of leucocytes to the joints.

 PMID:10491366

  19. Laricitrin suppresses increased benzo(a)pyrene-induced lung tumor-associated monocyte-derived dendritic cell cancer progression

    PubMed Central

    CHANG, WEI-AN; HUNG, JEN-YU; TSAI, YING-MING; HSU, YA-LING; CHIANG, HUNG-HSING; CHOU, SHAH-HWA; HUANG, MING-SHYAN; KUO, PO-LIN

    2016-01-01

    Benzo(a)pyrene (BaP) stimulates lung cancer cells, promoting monocyte-derived dendritic cells to secrete soluble factors, including heparin binding-epidermal growth factor and C-X-C motif chemokine 5. The secretions from monocyte-derived dendritic cells stimulate the progression of lung cancer cells, including the migration and invasion of cells. To the best of our knowledge, these secretions remain unknown, and require additional study. The present study identified that treatment with BaP-H1395-tumor-associated dendritic cell-conditioned medium had the most marked effect on cell migration and invasion. This result may be associated with the female gender, stage 2 adenocarcinoma or mutation of the proto-oncogene B-Raf (BRAF), according to the cell line background. Laricitrin, a dietary flavonoid derivative present in grapes and red wine, suppresses certain factors and decreases the progression of lung cancer cells that are promoted by BaP in the lung cancer tumor microenvironment. The results of the present study suggest that prolonged exposure to BaP exacerbates lung cancer, particularly in female lung cancer patients with the BRAF mutation, but that laricitrin may ameliorate this effect. PMID:26998077

  20. Activated Human Mast Cells Induce LOX-1-Specific Scavenger Receptor Expression in Human Monocyte-Derived Macrophages

    PubMed Central

    Alanne-Kinnunen, Mervi; Lappalainen, Jani; Öörni, Katariina; Kovanen, Petri T.

    2014-01-01

    Objective Activated mast cells in atherosclerotic lesions degranulate and release bioactive compounds capable of regulating atherogenesis. Here we examined the ability of activated human primary mast cells to regulate the expression of the major scavenger receptors in cultured human primary monocyte-derived macrophages (HMDMs). Results Components released by immunologically activated human primary mast cells induced a transient expression of lectin-like oxidized LDL receptor (LOX-1) mRNA in HMDMs, while the expression of two other scavenger receptors, MSR1 and CD36, remained unaffected. The LOX-1-inducing secretory components were identified as histamine, tumor necrosis factor alpha (TNF-α), and transforming growth factor beta (TGF-β1), which exhibited a synergistic effect on LOX-1 mRNA expression. Histamine induced a transient expression of LOX-1 protein. Mast cell –induced increase in LOX-1 expression was not associated with increased uptake of oxidized LDL by the macrophages. Conclusions Mast cell-derived histamine, TNF-α, and TGF-β1 act in concert to induce a transient increase in LOX-1 expression in human primary monocyte-derived macrophages. The LOX-1-inducing activity potentially endows mast cells a hitherto unrecognized role in the regulation of innate immune reactions in atherogenesis. PMID:25250731

  1. Expression of ESE-3 Isoforms in Immunogenic and Tolerogenic Human Monocyte-Derived Dendritic Cells

    PubMed Central

    Sprater, Florian; Hovden, Arnt-Ove; Appel, Silke

    2012-01-01

    Dendritic cells (DC) are the only hematopoietic cells expressing the epithelial specific Ets transcription factor ESE-3. Here we analyzed presence and quantity of isoforms ESE-3a, ESE-3b and ESE-3j in various immunogenic and tolerogenic human monocyte-derived DC (moDC) and blood DC populations using quantitative real time PCR and immunoblot analyses. ESE-3a and ESE-3b were detectable in all moDC populations with ESE-3b being the main transcript. ESE-3b expression was upregulated in immunogenic moDC and downregulated in tolerogenic moDC compared to immature moDC. ESE-3a had similar transcript levels in immature and immunogenic moDC and had very low levels in tolerogenic moDC. In blood DC populations only splice variant ESE-3b was detectable. ESE-3j was not detectable in any of the DC populations. These findings suggest that ESE-3b is the functionally most important ESE-3 isoform in DC. PMID:23185370

  2. Expression of ESE-3 isoforms in immunogenic and tolerogenic human monocyte-derived dendritic cells.

    PubMed

    Sprater, Florian; Hovden, Arnt-Ove; Appel, Silke

    2012-01-01

    Dendritic cells (DC) are the only hematopoietic cells expressing the epithelial specific Ets transcription factor ESE-3. Here we analyzed presence and quantity of isoforms ESE-3a, ESE-3b and ESE-3j in various immunogenic and tolerogenic human monocyte-derived DC (moDC) and blood DC populations using quantitative real time PCR and immunoblot analyses. ESE-3a and ESE-3b were detectable in all moDC populations with ESE-3b being the main transcript. ESE-3b expression was upregulated in immunogenic moDC and downregulated in tolerogenic moDC compared to immature moDC. ESE-3a had similar transcript levels in immature and immunogenic moDC and had very low levels in tolerogenic moDC. In blood DC populations only splice variant ESE-3b was detectable. ESE-3j was not detectable in any of the DC populations. These findings suggest that ESE-3b is the functionally most important ESE-3 isoform in DC. PMID:23185370

  3. Distinct Transcriptional Programs Control Cross-Priming in Classical and Monocyte-Derived Dendritic Cells.

    PubMed

    Briseño, Carlos G; Haldar, Malay; Kretzer, Nicole M; Wu, Xiaodi; Theisen, Derek J; Kc, Wumesh; Durai, Vivek; Grajales-Reyes, Gary E; Iwata, Arifumi; Bagadia, Prachi; Murphy, Theresa L; Murphy, Kenneth M

    2016-06-14

    Both classical DCs (cDCs) and monocyte-derived DCs (Mo-DCs) are capable of cross-priming CD8(+) T cells in response to cell-associated antigens. We found that Ly-6C(hi)TREML4(-) monocytes can differentiate into Zbtb46(+) Mo-DCs in response to granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4) but that Ly-6C(hi)TREML4(+) monocytes were committed to differentiate into Ly-6C(lo)TREML4(+) monocytes. Differentiation of Zbtb46(+) Mo-DCs capable of efficient cross-priming required both GM-CSF and IL-4 and was accompanied by the induction of Batf3 and Irf4. However, monocytes require IRF4, but not BATF3, to differentiate into Zbtb46(+) Mo-DCs capable of cross-priming CD8(+) T cells. Instead, Irf4(-/-) monocytes differentiate into macrophages in response to GM-CSF and IL-4. Thus, cDCs and Mo-DCs require distinct transcriptional programs of differentiation in acquiring the capacity to prime CD8(+) T cells. These differences may be of consideration in the use of therapeutic DC vaccines based on Mo-DCs. PMID:27264183

  4. IRF5 Risk Polymorphisms Contribute to Inter-Individual Variance in Pattern-Recognition Receptor-Mediated Cytokine Secretion in Human Monocyte-Derived Cells

    PubMed Central

    Hedl, Matija; Abraham, Clara

    2012-01-01

    Monocyte-derived cells display highly variable cytokine secretion upon pattern-recognition receptor (PRR) stimulation across individuals; such variability likely affects inter-individual inflammatory/autoimmune disease susceptibility. To define mechanisms for this heterogeneity, we examined pattern recognition receptor (PRR)-induced monocyte-derived-cell cytokine secretion from a large cohort healthy individuals. Although cytokine secretion ranged widely among individuals, the magnitude of cytokine induction after individual Nod2 and TLR2 stimulation (a cohort of 86 individuals) or stimulation of multiple TLRs (a cohort of 77 individuals), either alone or in combination with Nod2, was consistent intra-individually across these stimuli. Nod2 and TLRs signal through interferon-regulatory-factor-5 (IRF5) and common IRF5 polymorphisms confer risk for autoimmunity. We find that cells from rs2004640 IRF5 risk-associated allele carriers secrete increased cytokines upon individual or synergistic PRR stimulation in a gene dose- and ligand dose-dependent manner in both monocyte-derived dendritic cells and macrophages. IRF5 expression knockdown in IRF5-risk-allele carrier cells significantly decreases PRR-induced cytokines. Moreover, we find that IRF5 knockdown profoundly decreases Nod2-mediated MAPK and NF-κB pathway activation, whereas the PI3K and mTOR pathways are not impaired. Finally, the IRF5 rs2004640 polymorphism is a major determinant of the variance (r2=0.53) in Nod2-induced cytokine secretion by monocyte-derived cells from different individuals. We therefore show a profound contribution of a single gene to the variance in inter-individual PRR-induced cytokines. The hyper-responsiveness of IRF5 disease-associated polymorphisms to a wide spectrum of microbial triggers has broad implications on global immunological responses, host defenses against pathogens and inflammatory/autoimmune disease susceptibility. PMID:22544929

  5. No impairment of monocyte-derived Langerhans cell phenotype or function in early-onset psoriasis

    PubMed Central

    Shaw, F L; Kimber, I; Begum, R; Cumberbatch, M; Dearman, R J; Griffiths, C E M

    2012-01-01

    Background Migration of epidermal Langerhans cells (LCs) in response to the cytokines interleukin (IL)-1β and tumour necrosis factor (TNF)-α is impaired in uninvolved skin of patients with early-onset psoriasis. Aim To investigate whether this impairment is a reflection of a systemic defect in dendritic cells (DCs), using an established model of monocyte-derived LC-like cells (mLCs). Methods CD14+ monocytes isolated from both patients with psoriasis and healthy control volunteers were cultured in a cytokine cocktail for 5 days to promote their differentiation into mLCs, then stimulated for 24 h with TNF-α, IL-1β (both 100 ng/mL) or medium alone. Cellular surface protein expression was quantified by flow cytometry, and the ability of cells to migrate to media supplemented with C-C motif ligand (CCL)19 was assessed using a Transwell migration assay. The cytokine and chemokine content of supernatants was analysed by cytokine array. Results CD14+ cells acquired an LC-like phenotype with high expression of CD1a and major histocompatibility complex (MHC) class II. There were no differences in the expression of activation markers or in the secretion of cytokines by mLCs isolated from patients with psoriasis and those isolated from healthy controls. Moreover, mLCs isolated from both groups displayed comparable ability to migrate in vitro. Conclusions These data suggest that the failure of LCs to migrate in response to stimulation in patients with psoriasis is not attributable to a systemic defect in DC function, but is rather a reflection of local changes in the epidermal microenvironment. PMID:21933242

  6. Replication of Salmonella enterica Serovar Typhimurium in Human Monocyte-Derived Macrophages.

    PubMed

    Lathrop, Stephanie K; Binder, Kelsey A; Starr, Tregei; Cooper, Kendal G; Chong, Audrey; Carmody, Aaron B; Steele-Mortimer, Olivia

    2015-07-01

    Salmonella enterica serovar Typhimurium is a common cause of food-borne gastrointestinal illness, but additionally it causes potentially fatal bacteremia in some immunocompromised patients. In mice, systemic spread and replication of the bacteria depend upon infection of and replication within macrophages, but replication in human macrophages is not widely reported or well studied. In order to assess the ability of Salmonella Typhimurium to replicate in human macrophages, we infected primary monocyte-derived macrophages (MDM) that had been differentiated under conditions known to generate different phenotypes. We found that replication in MDM depends greatly upon the phenotype of the cells, as M1-skewed macrophages did not allow replication, while M2a macrophages and macrophages differentiated with macrophage colony-stimulating factor (M-CSF) alone (termed M0) did. We describe how additional conditions that alter the macrophage phenotype or the gene expression of the bacteria affect the outcome of infection. In M0 MDM, the temporal expression of representative genes from Salmonella pathogenicity islands 1 and 2 (SPI1 and SPI2) and the importance of the PhoP/Q two-component regulatory system are similar to what has been shown in mouse macrophages. However, in contrast to mouse macrophages, where replication is SPI2 dependent, we observed early SPI2-independent replication in addition to later SPI2-dependent replication in M0 macrophages. Only SPI2-dependent replication was associated with death of the host cell at later time points. Altogether, our results reveal a very nuanced interaction between Salmonella and human macrophages. PMID:25895967

  7. Human cytomegalovirus inhibits maturation and impairs function of monocyte-derived dendritic cells.

    PubMed

    Moutaftsi, Magdalena; Mehl, Anja M; Borysiewicz, Leszek K; Tabi, Zsuzsanna

    2002-04-15

    Dendritic cells (DCs) play a pivotal role in the generation of virus-specific cytotoxic T-cell responses, but some viruses can render DCs inefficient in stimulating T cells. We studied whether infection of DCs with human cytomegalovirus (HCMV) results in a suppression of DC function which may assist HCMV in establishing persistence. The effect of HCMV infection on the phenotype and function of monocyte-derived DCs and on their ability to mature following infection with an endothelial cell-adapted clinical HCMV isolate were studied. HCMV infection induced no maturation of DCs; instead, it efficiently down-regulated the expression of surface major histocompatibility complex (MHC) class I, CD40, and CD80 molecules. Slight down-regulation of MHC class II and CD86 molecules was also observed. Lipopolysaccharide (LPS)-induced maturation of infected DCs was strongly inhibited, as indicated by lower levels of surface expression of MHC class I, class II, costimulatory, and CD83 molecules. The down-regulation or inhibition of these surface markers occurred only in HCMV antigen-positive DCs. DCs produced no interleukin 12 (IL-12) and only low levels of tumor necrosis factor alpha (TNF-alpha) upon HCMV infection. Furthermore, cytokine production upon stimulation with LPS or CD40L was significantly impaired. Inhibition of cytokine production did not depend on viral gene expression as UV-irradiated HCMV resulted in the same effect. Proliferation and cytotoxicity of T cells specific to a recall antigen presented by DCs were also reduced when DCs were HCMV infected. This study shows that HCMV inhibits DC function, revealing a powerful viral strategy to delay or prevent the generation of virus-specific cytotoxic T cells. PMID:11929782

  8. Replication of Salmonella enterica Serovar Typhimurium in Human Monocyte-Derived Macrophages

    PubMed Central

    Lathrop, Stephanie K.; Binder, Kelsey A.; Starr, Tregei; Cooper, Kendal G.; Chong, Audrey; Carmody, Aaron B.

    2015-01-01

    Salmonella enterica serovar Typhimurium is a common cause of food-borne gastrointestinal illness, but additionally it causes potentially fatal bacteremia in some immunocompromised patients. In mice, systemic spread and replication of the bacteria depend upon infection of and replication within macrophages, but replication in human macrophages is not widely reported or well studied. In order to assess the ability of Salmonella Typhimurium to replicate in human macrophages, we infected primary monocyte-derived macrophages (MDM) that had been differentiated under conditions known to generate different phenotypes. We found that replication in MDM depends greatly upon the phenotype of the cells, as M1-skewed macrophages did not allow replication, while M2a macrophages and macrophages differentiated with macrophage colony-stimulating factor (M-CSF) alone (termed M0) did. We describe how additional conditions that alter the macrophage phenotype or the gene expression of the bacteria affect the outcome of infection. In M0 MDM, the temporal expression of representative genes from Salmonella pathogenicity islands 1 and 2 (SPI1 and SPI2) and the importance of the PhoP/Q two-component regulatory system are similar to what has been shown in mouse macrophages. However, in contrast to mouse macrophages, where replication is SPI2 dependent, we observed early SPI2-independent replication in addition to later SPI2-dependent replication in M0 macrophages. Only SPI2-dependent replication was associated with death of the host cell at later time points. Altogether, our results reveal a very nuanced interaction between Salmonella and human macrophages. PMID:25895967

  9. Effect of a standardized liver and spleen fraction of peptides on the differentiation of human monocyte-derived macrophages.

    PubMed

    Spessotto, P; Bulla, R; Mittenzwei, H; Dri, P

    1994-06-01

    The effect of Factor AF2 (AF2), a standardized fraction of peptides with a molecular weight of < 10,000 Dalton obtained from livers and spleens of newborn lambs, on the differentiation of human monocyte-derived macrophages was studied, in view of the central role played by these cells in inflammation and tumor cytotoxicity. The results show that the drug 1. increases the cell density of cultures, 2. favours the morphologic differentiation of monocytes into macrophages, and 3. increases the macrophages phagocytic capacity. The first two effects are observed when monocytes are cultured in 1% serum but not in 10% serum while the enhancement of phagocytic activity is detected at both serum concentrations. PMID:8053979

  10. Non-identical twins - microglia and monocyte-derived macrophages in acute injury and autoimmune inflammation.

    PubMed

    Jung, Steffen; Schwartz, Michal

    2012-01-01

    The brain has been commonly regarded as a "tissue behind walls." Appearance of immune cells in the brain has been taken as a sign of pathology. Moreover, since infiltrating monocyte-derived macrophages and activated resident microglia were indistinguishable by conventional means, both populations were considered together as inflammatory cells that should be mitigated. Yet, because the microglia permanently reside in the brain, attributing to them negative properties evoked an ongoing debate; why cells that are supposed to be the brain guardians acquire only destructive potential? Studies over the last two decades in the immune arena in general, and in the context of central nervous system pathology in particular, have resulted in a paradigm shift toward a more balanced appreciation of the contributions of immune cells in the context of brain maintenance and repair, and toward the recognition of distinct roles of resident microglia and infiltrating monocyte-derived macrophages. PMID:22566968

  11. The effect of short-chain fatty acids on human monocyte-derived dendritic cells.

    PubMed

    Nastasi, Claudia; Candela, Marco; Bonefeld, Charlotte Menné; Geisler, Carsten; Hansen, Morten; Krejsgaard, Thorbjørn; Biagi, Elena; Andersen, Mads Hald; Brigidi, Patrizia; Ødum, Niels; Litman, Thomas; Woetmann, Anders

    2015-01-01

    The gut microbiota is essential for human health and plays an important role in the pathogenesis of several diseases. Short-chain fatty acids (SCFA), such as acetate, butyrate and propionate, are end-products of microbial fermentation of macronutrients that distribute systemically via the blood. The aim of this study was to investigate the transcriptional response of immature and LPS-matured human monocyte-derived DC to SCFA. Our data revealed distinct effects exerted by each individual SCFA on gene expression in human monocyte-derived DC, especially in the mature ones. Acetate only exerted negligible effects, while both butyrate and propionate strongly modulated gene expression in both immature and mature human monocyte-derived DC. An Ingenuity pathway analysis based on the differentially expressed genes suggested that propionate and butyrate modulate leukocyte trafficking, as SCFA strongly reduced the release of several pro-inflammatory chemokines including CCL3, CCL4, CCL5, CXCL9, CXCL10, and CXCL11. Additionally, butyrate and propionate inhibited the expression of lipopolysaccharide (LPS)-induced cytokines such as IL-6 and IL-12p40 showing a strong anti-inflammatory effect. This work illustrates that bacterial metabolites far from the site of their production can differentially modulate the inflammatory response and generally provides new insights into host-microbiome interactions. PMID:26541096

  12. Differential Activation of Infiltrating Monocyte-Derived Cells After Mild and Severe Traumatic Brain Injury.

    PubMed

    Trahanas, Diane M; Cuda, Carla M; Perlman, Harris; Schwulst, Steven J

    2015-03-01

    Microglia are the resident innate immune cells of the brain. Although embryologically and functionally distinct, they are morphologically similar to peripheral monocyte-derived cells, resulting in a poor ability to discriminate between the two cell types. The purpose of this study was to develop a rapid and reliable method to simultaneously characterize, quantify, and discriminate between whole populations of myeloid cells from the brain in a murine model of traumatic brain injury. Male C57BL/6 mice underwent traumatic brain injury (n = 16) or sham injury (n = 14). Brains were harvested at 24 h after injury. Multiparameter flow cytometry and sequential gating analysis were performed, allowing for discrimination between microglia and infiltrating leukocytes as well as for the characterization and quantification of individual subtypes within the infiltrating population. The proportion of infiltrating leukocytes within the brain increased with the severity of injury, and the predominant cell types within the infiltrating population were monocyte derived (P = 0.01). In addition, the severity of injury altered the overall makeup of the infiltrating monocyte-derived cells. In conclusion, we describe a flow cytometry-based technique for gross discrimination between infiltrating leukocytes and microglia as well as the ability to simultaneously characterize and quantify individual myeloid subtypes and their maturation states within these populations. PMID:26091024

  13. Differential activation of infiltrating monocyte-derived cells after mild and severe traumatic brain injury

    PubMed Central

    Trahanas, Diane M.; Cuda, Carla M.; Perlman, Harris; Schwulst, Steven J.

    2014-01-01

    Microglia are the resident innate immune cells of the brain. Although embryologically and functionally distinct, they are morphologically similar to peripheral monocyte-derived cells resulting in a poor ability to discriminate between the two cell types. The purpose of this study was to develop a rapid and reliable method to simultaneously characterize, quantify, and discriminate between whole populations of myeloid cells from the brain in a murine model of traumatic brain injury (TBI). Male C57BL/6 mice underwent TBI (n=16) or sham injury (n=14). Brains were harvested at 24 hours post injury. Multiparameter flow cytometry and sequential gating analysis was performed allowing for discrimination between microglia and infiltrating leukocytes as well as for the characterization and quantification of individual subtypes within the infiltrating population. The proportion of infiltrating leukocytes within the brain increased with the severity of injury and the predominate cell types within the infiltrating population were monocyte-derived (p=0.01). Additionally, the severity of injury altered the overall makeup of the infiltrating monocyte-derived cells. In conclusion, we describe a flow cytometry based technique for gross discrimination between infiltrating leukocytes and microglia as well as the ability to simultaneously characterize and quantify individual myeloid subtypes and their maturation states within these populations. PMID:26091024

  14. SAMHD1 Limits HIV-1 Antigen Presentation by Monocyte-Derived Dendritic Cells

    PubMed Central

    Bruel, Timothée; Cardinaud, Sylvain; Porrot, Françoise; Prado, Julia G.; Moris, Arnaud

    2015-01-01

    ABSTRACT Monocyte-derived dendritic cells (MDDC) stimulate CD8+ cytotoxic T lymphocytes (CTL) by presenting endogenous and exogenous viral peptides via major histocompatibility complex class I (MHC-I) molecules. MDDC are poorly susceptible to HIV-1, in part due to the presence of SAMHD1, a cellular enzyme that depletes intracellular deoxynucleoside triphosphates (dNTPs) and degrades viral RNA. Vpx, an HIV-2/SIVsm protein absent from HIV-1, antagonizes SAMHD1 by inducing its degradation. The impact of SAMHD1 on the adaptive cellular immune response remains poorly characterized. Here, we asked whether SAMHD1 modulates MHC-I-restricted HIV-1 antigen presentation. Untreated MDDC or MDDC pretreated with Vpx were exposed to HIV-1, and antigen presentation was examined by monitoring the activation of an HIV-1 Gag-specific CTL clone. SAMHD1 depletion strongly enhanced productive infection of MDDC as well as endogenous HIV-1 antigen presentation. Time-lapse microscopy analysis demonstrated that in the absence of SAMHD1, the CTL rapidly killed infected MDDC. We also report that various transmitted/founder (T/F) HIV-1 strains poorly infected MDDC and, as a consequence, did not stimulate CTL. Vesicular stomatitis virus glycoprotein (VSV-G) pseudotyping of T/F alleviated a block in viral entry and induced antigen presentation only in the absence of SAMHD1. Furthermore, by using another CTL clone that mostly recognizes incoming HIV-1 antigens, we demonstrate that SAMHD1 does not influence exogenous viral antigen presentation. Altogether, our results demonstrate that the antiviral activity of SAMHD1 impacts antigen presentation by DC, highlighting the link that exists between restriction factors and adaptive immune responses. IMPORTANCE Upon viral infection, DC may present antigens derived from incoming viral material in the absence of productive infection of DC or from newly synthesized viral proteins. In the case of HIV, productive infection of DC is blocked at an early

  15. Matrix metalloproteinase-12 gene regulation by a PPAR alpha agonist in human monocyte-derived macrophages

    SciTech Connect

    Souissi, Imen Jguirim; Billiet, Ludivine; Cuaz-Perolin, Clarisse; Rouis, Mustapha

    2008-11-01

    MMP-12, a macrophage-specific matrix metalloproteinase with large substrate specificity, has been reported to be highly expressed in mice, rabbits and human atherosclerotic lesions. Increased MMP-12 from inflammatory macrophages is associated with several degenerative diseases such as atherosclerosis. In this manuscript, we show that IL-1{beta}, a proinflammatory cytokine found in atherosclerotic plaques, increases both mRNA and protein levels of MMP-12 in human monocyte-derived macrophages (HMDM). Since peroxisome proliferator-activated receptors (PPARs), such as PPAR{alpha} and PPAR{gamma}, are expressed in macrophages and because PPAR activation exerts an anti-inflammatory effect on vascular cells, we have investigated the effect of PPAR{alpha} and {gamma} isoforms on MMP-12 regulation in HMDM. Our results show that MMP-12 expression (mRNA and protein) is down regulated in IL-1{beta}-treated macrophages only in the presence of a specific PPAR{alpha} agonist, GW647, in a dose-dependent manner. In contrast, this inhibitory effect was abolished in IL-1{beta}-stimulated peritoneal macrophages isolated from PPAR{alpha}{sup -/-} mice and treated with the PPAR{alpha} agonist, GW647. Moreover, reporter gene transfection experiments using different MMP-12 promoter constructs showed a reduction of the promoter activities by {approx} 50% in IL-1{beta}-stimulated PPAR{alpha}-pre-treated cells. However, MMP-12 promoter analysis did not reveal the presence of a PPRE response element. The IL-1{beta} effect is known to be mediated through the AP-1 binding site. Mutation of the AP-1 site, located at - 81 in the MMP-12 promoter region relative to the transcription start site, followed by transfection analysis, gel shift and ChIP experiments revealed that the inhibitory effect was the consequence of the protein-protein interaction between GW 647-activated PPAR{alpha} and c-Fos or c-Jun transcription factors, leading to inhibition of their binding to the AP-1 motif. These studies

  16. Phenotypic dynamics of microglial and monocyte-derived cells in glioblastoma-bearing mice.

    PubMed

    Ricard, Clément; Tchoghandjian, Aurélie; Luche, Hervé; Grenot, Pierre; Figarella-Branger, Dominique; Rougon, Geneviève; Malissen, Marie; Debarbieux, Franck

    2016-01-01

    Inflammatory cells, an integral component of tumor evolution, are present in Glioblastomas multiforme (GBM). To address the cellular basis and dynamics of the inflammatory microenvironment in GBM, we established an orthotopic syngenic model by grafting GL261-DsRed cells in immunocompetent transgenic LysM-EGFP//CD11c-EYFP reporter mice. We combined dynamic spectral two-photon imaging with multiparametric cytometry and multicolor immunostaining to characterize spatio-temporal distribution, morphology and activity of microglia and blood-derived infiltrating myeloid cells in live mice. Early stages of tumor development were dominated by microglial EYFP(+) cells invading the tumor, followed by massive recruitment of circulating LysM-EGFP(+) cells. Fluorescent invading cells were conventional XCR1(+) and monocyte-derived dendritic cells distributed in subpopulations of different maturation stages, located in different areas relative to the tumor core. The lethal stage of the disease was characterized by the progressive accumulation of EGFP(+)/EYFP(+) monocyte-derived dendritic cells. This local phenotypic regulation of monocyte subtypes marked a transition in the immune response. PMID:27193333

  17. Phenotypic dynamics of microglial and monocyte-derived cells in glioblastoma-bearing mice

    PubMed Central

    Ricard, Clément; Tchoghandjian, Aurélie; Luche, Hervé; Grenot, Pierre; Figarella-Branger, Dominique; Rougon, Geneviève; Malissen, Marie; Debarbieux, Franck

    2016-01-01

    Inflammatory cells, an integral component of tumor evolution, are present in Glioblastomas multiforme (GBM). To address the cellular basis and dynamics of the inflammatory microenvironment in GBM, we established an orthotopic syngenic model by grafting GL261-DsRed cells in immunocompetent transgenic LysM-EGFP//CD11c-EYFP reporter mice. We combined dynamic spectral two-photon imaging with multiparametric cytometry and multicolor immunostaining to characterize spatio-temporal distribution, morphology and activity of microglia and blood-derived infiltrating myeloid cells in live mice. Early stages of tumor development were dominated by microglial EYFP+ cells invading the tumor, followed by massive recruitment of circulating LysM-EGFP+ cells. Fluorescent invading cells were conventional XCR1+ and monocyte-derived dendritic cells distributed in subpopulations of different maturation stages, located in different areas relative to the tumor core. The lethal stage of the disease was characterized by the progressive accumulation of EGFP+/EYFP+ monocyte-derived dendritic cells. This local phenotypic regulation of monocyte subtypes marked a transition in the immune response. PMID:27193333

  18. Monocyte-derived extracellular Nampt-dependent biosynthesis of NAD(+) protects the heart against pressure overload.

    PubMed

    Yano, Masamichi; Akazawa, Hiroshi; Oka, Toru; Yabumoto, Chizuru; Kudo-Sakamoto, Yoko; Kamo, Takehiro; Shimizu, Yu; Yagi, Hiroki; Naito, Atsuhiko T; Lee, Jong-Kook; Suzuki, Jun-ichi; Sakata, Yasushi; Komuro, Issei

    2015-01-01

    Nicotinamide phosphoribosyltransferase (Nampt) catalyzes the rate-limiting step in the salvage pathway for nicotinamide adenine dinucleotide (NAD(+)) biosynthesis, and thereby regulates the deacetylase activity of sirtuins. Here we show accommodative regulation of myocardial NAD(+) by monocyte-derived extracellular Nampt (eNampt), which is essential for hemodynamic compensation to pressure overload. Although intracellular Nampt (iNampt) expression was decreased in pressure-overloaded hearts, myocardial NAD(+) concentration and Sirt1 activity were preserved. In contrast, iNampt was up-regulated in spleen and monocytes, and circulating eNampt protein and nicotinamide mononucleotide (NMN), a key precursor of NAD(+), were significantly increased. Pharmacological inhibition of Nampt by FK866 or depletion of monocytes/macrophages by clodronate liposomes disrupted the homeostatic mechanism of myocardial NAD(+) levels and NAD(+)-dependent Sirt1 activity, leading to susceptibility to cardiomyocyte apoptosis and cardiac decompensation in pressure-overloaded mice. These biochemical and hemodynamic defects were prevented by systemic administration of NMN. Our studies uncover a crucial role of monocyte-derived eNampt in myocardial adaptation to pressure overload, and highlight a potential intervention controlling myocardial NAD(+) against heart failure. PMID:26522369

  19. Mycobacterium leprae upregulates IRGM expression in monocytes and monocyte-derived macrophages.

    PubMed

    Yang, Degang; Chen, Jia; Zhang, Linglin; Cha, Zhanshan; Han, Song; Shi, Weiwei; Ding, Ru; Ma, Lan; Xiao, Hong; Shi, Chao; Jing, Zhichun; Song, Ningjing

    2014-08-01

    Leprosy is caused by the infection of Mycobacterium leprae, which evokes a strong inflammatory response and leads to nerve damage. Immunity-related GTPase family M protein (IRGM) plays critical roles in controlling inflammation. The objective of the study was to investigate whether IRGM is involved in the infection of M. leprae. Levels of IRGM were assessed in M. leprae-infected CD4(+) T cells, monocytes, and monocyte-derived macrophages. Data revealed that both protein and mRNA levels of IRGM were increased in monocytes after M. leprae infection. Interestingly, monocyte-derived macrophages showed more prominent IRGM expression with M. leprae infection, whereas the bacteria did not affect IRGM in CD4(+) T cells. Furthermore, we assessed levels of IRGM in CD4(+) T cells and monocytes from 78 leprosy patients and 40 healthy controls, and observed upregulated protein level of IRGM in the monocytes from leprosy patients. Also, IRGM expression was inversely correlated with the severity of the disease. These findings suggested a close involvement of IRGM in M. leprae infection and indicated a potential mechanism of defending M. leprae infection. PMID:24469081

  20. Serum IL-10 from systemic lupus erythematosus patients suppresses the differentiation and function of monocyte-derived dendritic cells

    PubMed Central

    Sun, Zhida; Zhang, Rong; Wang, Huijuan; Jiang, Pengtao; Zhang, Jiangquan; Zhang, Mingshun; Gu, Lei; Yang, Xiaofan; Zhang, Miaojia; Ji, Xiaohui

    2012-01-01

    The role played by cytokines, other than interferon (IFN)-α, in the differentiation and function of dendritic cells (DCs) in systemic lupus erythematosus (SLE), remains unclear. Serum interleukin-10 (IL-10) levels are generally elevated in SLE patients, which might modulate the differentiation of DCs. In this study, DCs were induced from monocytes either by transendothelial trafficking or by culture with granulocyte-macrophage colony-stimulating factor (GM-CSF) + IL-4 + tumor necrosis factor (TNF)-α. Both systems were used to investigate the effects of elevated serum IL-10 level on DC differentiation in SLE patients. The results showed that monocyte-derived DCs induced by either SLE serum or exogenous IL-10 reduced the expression of human leukocyte antigen (HLA)-DR and CD80, decreased IL-12p40 level, and increased IL-10 level, and exhibited an impaired capacity to stimulate allogenic T-cell proliferation. These results indicate that serum IL-10 may be involved in the pathogenesis of SLE by modulating the differentiation and function of DCs. PMID:23554785

  1. Effect of size of man-made and natural mineral fibers on chemiluminescent response in human monocyte-derived macrophages.

    PubMed Central

    Ohyama, M; Otake, T; Morinaga, K

    2001-01-01

    Fiber size is an important factor in the tumorigenicity of various mineral fibers and asbestos fibers in animal experiments. We examined the time course of the ability to induce lucigenin-dependent chemiluminescence (CL) from human monocyte-derived macrophages exposed to Japan Fibrous Material standard reference samples (glass wool, rock wool, micro glass fiber, two types of refractory ceramic fiber, refractory mullite fiber, potassium titanium whisker, silicon carbide whisker, titanium oxide whisker, and wollastonite). We determined how fiber length or width might modify the response of cells. We found that the patterns of time-dependent increase of CL (sigmoid type) were similar for each sample except wollastonite. We observed a strong correlation between geometric-mean length and ability to induce CL in seven samples > 6 microm in length over the time course (largest r(2) = 0.9760). Although we also observed a close positive correlation between geometric-mean width and the ability to induce CL in eight samples < 1.8 microm in width at 15 min (r(2) = 0.8760), a sample of 2.4 microm in width had a low ability to induce CL. Moreover, the relationship between width and the rate of increase in ability to induce CL had a negative correlation at 30-60 min (largest r(2) = 0.7473). Our findings suggest that the release of superoxide from macrophages occurs nonspecifically for various types of mineral fibers depending on fiber length. PMID:11675268

  2. SAMHD1 Restricts HIV-1 Cell-to-Cell Transmission and Limits Immune Detection in Monocyte-Derived Dendritic Cells

    PubMed Central

    Puigdomènech, Isabel; Casartelli, Nicoletta; Porrot, Françoise

    2013-01-01

    SAMHD1 is a viral restriction factor expressed in dendritic cells and other cells, inhibiting infection by cell-free human immunodeficiency virus type 1 (HIV-1) particles. SAMHD1 depletes the intracellular pool of deoxynucleoside triphosphates, thus impairing HIV-1 reverse transcription and productive infection in noncycling cells. The Vpx protein from HIV-2 or simian immunodeficiency virus (SIVsm/SIVmac) antagonizes the effect of SAMHD1 by triggering its degradation. A large part of HIV-1 spread occurs through direct contacts between infected cells and bystander target cells. Here, we asked whether SAMHD1 impairs direct HIV-1 transmission from infected T lymphocytes to monocyte-derived dendritic cells (MDDCs). HIV-1-infected lymphocytes were cocultivated with MDDCs that have been pretreated or not with Vpx or with small interfering RNA against SAMHD1. We show that in the cocultures, SAMHD1 significantly inhibits productive cell-to-cell transmission to target MDDCs and prevents the type I interferon response and expression of the interferon-stimulated gene MxA. Therefore, SAMHD1, by controlling the sensitivity of MDDCs to HIV-1 infection during intercellular contacts, impacts their ability to sense the virus and to trigger an innate immune response. PMID:23269793

  3. Monocyte-Derived Dendritic Cells Are Essential for CD8+ T Cell Activation and Antitumor Responses After Local Immunotherapy

    PubMed Central

    Kuhn, Sabine; Yang, Jianping; Ronchese, Franca

    2015-01-01

    Tumors harbor several populations of dendritic cells (DCs) with the ability to prime tumor-specific T cells. However, these T cells mostly fail to differentiate into armed effectors and are unable to control tumor growth. We have previously shown that treatment with immunostimulatory agents at the tumor site can activate antitumor immune responses and is associated with the appearance of a population of monocyte-derived DCs (moDCs) in the tumor and tumor-draining lymph node (dLN). Here, we use depletion of DCs or monocytes and monocyte transfer to show that these moDCs are critical to the activation of antitumor immune responses. Treatment with the immunostimulatory agents monosodium urate crystals and Mycobacterium smegmatis induced the accumulation of monocytes in the dLN, their upregulation of CD11c and MHCII, and expression of iNOS, TNFα, and IL12p40. Blocking monocyte entry into the lymph node and tumor through neutralization of the chemokine CCL2 or inhibition of colony-stimulating factor-1 receptor signaling prevented the generation of moDCs, the infiltration of tumor-specific T cells into the tumor, and antitumor responses. In a reciprocal fashion, monocytes transferred into mice depleted of CD11c+ cells were sufficient to rescue CD8+ T cell priming in lymph node and delay tumor growth. Thus, monocytes exposed to the appropriate conditions become powerful activators of tumor-specific CD8+ T cells and antitumor immunity. PMID:26635798

  4. Annexin 2: a novel human immunodeficiency virus type 1 Gag binding protein involved in replication in monocyte-derived macrophages.

    PubMed

    Ryzhova, Elena V; Vos, Robin M; Albright, Andrew V; Harrist, Alexia V; Harvey, Thomas; González-Scarano, Francisco

    2006-03-01

    Human immunodeficiency virus (HIV) replication in the major natural target cells, CD4+ T lymphocytes and macrophages, is parallel in many aspects of the virus life cycle. However, it differs as to viral assembly and budding, which take place on plasma membranes in T cells and on endosomal membranes in macrophages. It has been postulated that cell type-specific host factors may aid in directing viral assembly to distinct destinations. In this study we defined annexin 2 (Anx2) as a novel HIV Gag binding partner in macrophages. Anx2-Gag binding was confined to productively infected macrophages and was not detected in quiescently infected monocyte-derived macrophages (MDM) in which an HIV replication block was mapped to the late stages of the viral life cycle (A. V. Albright, R. M. Vos, and F. Gonzalez-Scarano, Virology 325:328-339, 2004). We demonstrate that the Anx2-Gag interaction likely occurs at the limiting membranes of late endosomes/multivesicular bodies and that Anx2 depletion is associated with a significant decline in the infectivity of released virions; this coincided with incomplete Gag processing and inefficient incorporation of CD63. Cumulatively, our data suggest that Anx2 is essential for the proper assembly of HIV in MDM. PMID:16501079

  5. Immunomodulatory effects of adult Haemonchus contortus excretory/secretory products on human monocyte-derived dendritic cells.

    PubMed

    Rehman, Z U; Knight, J S; Koolaard, J; Simpson, H V; Pernthaner, A

    2015-12-01

    The levels of expression of surface molecules and release of cytokines and chemokines of human monocyte-derived dendritic cells were determined after their exposure to adult H. contortus excretory/secretory (ES) products or a combination of ES products and bacterial lipopolysaccharide (LPS). Worm products provoked a weak response and only partial maturation of the dendritic cells, consistent with the hyporesponsiveness and more tolerogenic immune environment present in parasitized animals and humans. Co-stimulation with LPS demonstrated that H. contortus secretions, like those of other helminths, contain immunomodulators capable of reducing some aspects of the strong T(H)1/T(H)2 response evoked by bacterial LPS. There were significant reductions in the release of some cytokine/chemokines by LPS-stimulated mdDCs and a trend (although not significant at P < 0.05) for reduced expression levels of CD40, CD80 and HLA-DR. A prominent feature was the variability in responses of dendritic cells from the four donors, even on different days in repeat experiments, suggesting that generalized conclusions may be difficult to make, except in genetically related animals. Such observations may therefore be applicable only to restricted populations. In addition, previous exposure to parasites in a target population for immunomodulatory therapy may be an important factor in assessing the likelihood of adverse reactions or failures in the treatment to worm therapy. PMID:26457886

  6. An in vitro model to assess the immunosuppressive effect of tick saliva on the mobilization of inflammatory monocyte-derived cells.

    PubMed

    Vachiery, Nathalie; Puech, Carinne; Cavelier, Patricia; Rodrigues, Valérie; Aprelon, Rosalie; Lefrançois, Thierry; Martinez, Dominique; Epardaud, Mathieu

    2015-01-01

    Tick-borne pathogens cause potent infections. These pathogens benefit from molecules contained in tick saliva that have evolved to modulate host innate and adaptive immune responses. This is called "saliva-activated transmission" and enables tick-borne pathogens to evade host immune responses. Ticks feed on their host for relatively long periods; thus, mechanisms counteracting the inflammation-driven recruitment and activation of innate effector cells at the bite site, are an effective strategy to escape the immune response. Here, we developed an original in vitro model to evaluate and to characterize the immunomodulatory effects of tick saliva that prevent the establishment of a local inflammatory immune response. This model mimics the tick bite and enables the assessment of the effect of saliva on the inflammatory-associated dynamic recruitment of cells from the mononuclear phagocyte system. Using this model, we were able to recapitulate the dual effect of tick saliva on the mobilization of inflammatory monocyte-derived cells, i.e. (i) impaired recruitment of monocytes from the blood to the bite wound; and (ii) poor mobilization of monocyte-derived cells from the skin to the draining lymph node. This simple tool reconstitutes the effect of tick saliva in vivo, which we characterized in the mouse, and should enable the identification of important factors facilitating pathogen infection. Furthermore, this model may be applied to the characterization of any pathogen-derived immunosuppressive molecule affecting the establishment of the inflammatory immune response. PMID:26412247

  7. In vitro interaction of Stenotrophomonas maltophilia with human monocyte-derived dendritic cells

    PubMed Central

    Roscetto, Emanuela; Vitiello, Laura; Muoio, Rosa; Soriano, Amata A.; Iula, Vita D.; Vollaro, Antonio; Gregorio, Eliana De; Catania, Maria R.

    2015-01-01

    Stenotrophomonas maltophilia is increasingly identified as an opportunistic pathogen in immunocompromised, cancer and cystic fibrosis (CF) patients. Knowledge on innate immune responses to S. maltophilia and its potential modulation is poor. The present work investigated the ability of 12 clinical S. maltophilia strains (five from CF patients, seven from non-CF patients) and one environmental strain to survive inside human monocyte-derived dendritic cells (DCs). The effects of the bacteria on maturation of and cytokine secretion by DCs were also measured. S. maltophilia strains presented a high degree of heterogeneity in internalization and intracellular replication efficiencies as well as in the ability of S. maltophilia to interfere with normal DCs maturation. By contrast, all S. maltophilia strains were able to activate DCs, as measured by increase in the expression of surface maturation markers and proinflammatory cytokines secretion. PMID:26236302

  8. Oxidative metabolism in cord blood monocytes and monocyte-derived macrophages.

    PubMed Central

    Speer, C P; Ambruso, D R; Grimsley, J; Johnston, R B

    1985-01-01

    Little is known about phagocytosis-associated oxidative metabolism in mononuclear phagocytes from the human neonate. We investigated this phenomenon in monocytes from the cord blood of term newborn infants by measuring generation of superoxide anion (O2-) and hydroxyl radical (X OH) after stimulation with opsonized zymosan or phorbol myristate acetate. Production of these microbicidal oxygen metabolites by monocytes from neonates and healthy adult volunteers was equivalent. When cultured in the presence of the macrophage activator lipopolysaccharide or muramyl dipeptide, monocytes from neonates and adults differentiated into cells with the appearance of macrophages and with an enhanced capacity to release O2- compared with cells cultured in the absence of an activator. Monocyte-derived macrophages from neonates produced only slightly less O2- than did adult cells. Thus, unlike the cord blood neutrophil, which exhibits abnormalities in oxidative metabolism, the cord blood mononuclear phagocyte has a respiratory burst that is quantitatively comparable to that of the adult cell. PMID:2999001

  9. Divergent JAM-C Expression Accelerates Monocyte-Derived Cell Exit from Atherosclerotic Plaques

    PubMed Central

    Miljkovic-Licina, Marijana; Lee, Boris P.; Fischer, Nicolas; Fish, Richard J.; Kwak, Brenda; Fisher, Edward A.; Imhof, Beat A.

    2016-01-01

    Atherosclerosis, caused in part by monocytes in plaques, continues to be a disease that afflicts the modern world. Whilst significant steps have been made in treating this chronic inflammatory disease, questions remain on how to prevent monocyte and macrophage accumulation in atherosclerotic plaques. Junctional Adhesion Molecule C (JAM-C) expressed by vascular endothelium directs monocyte transendothelial migration in a unidirectional manner leading to increased inflammation. Here we show that interfering with JAM-C allows reverse-transendothelial migration of monocyte-derived cells, opening the way back out of the inflamed environment. To study the role of JAM-C in plaque regression we used a mouse model of atherosclerosis, and tested the impact of vascular JAM-C expression levels on monocyte reverse transendothelial migration using human cells. Studies in-vitro under inflammatory conditions revealed that overexpression or gene silencing of JAM-C in human endothelium exposed to flow resulted in higher rates of monocyte reverse-transendothelial migration, similar to antibody blockade. We then transplanted atherosclerotic, plaque-containing aortic arches from hyperlipidemic ApoE-/- mice into wild-type normolipidemic recipient mice. JAM-C blockade in the recipients induced greater emigration of monocyte-derived cells and further diminished the size of atherosclerotic plaques. Our findings have shown that JAM-C forms a one-way vascular barrier for leukocyte transendothelial migration only when present at homeostatic copy numbers. We have also shown that blocking JAM-C can reduce the number of atherogenic monocytes/macrophages in plaques by emigration, providing a novel therapeutic strategy for chronic inflammatory pathologies. PMID:27442505

  10. Expression and Function of Semaphorin 3A and Its Receptors in Human Monocyte-derived Macrophages

    PubMed Central

    Ji, Jong-Dae; Park-Min, Kyung-Hyun; Ivashkiv, Lionel B.

    2016-01-01

    Semaphorins are a large family of secreted and membrane-bound proteins. Recently, several roles of semaphorins in the immune system have emerged. Several semaphorins and their receptors are expressed in a variety of lymphoid and myeloid cells and affect immune cell functions, including cell proliferation, differentiation, chemotaxis, and cytokine production. However, the roles of class 3 semaphorins in human myeloid cells are not well known. Here we examined the regulation of expression of class 3 semaphorins and their receptors by inflammatory stimuli and their function in human macrophages. We show that the expression of Sema3A receptors (neuropilin-1 (NRP-1), NRP-2, plexin A1, plexin A2 and plexin A3) significantly increased during M-CSF-mediated differentiation of monocytes into macrophages under conditions that promote an M2 alternatively activated macrophage phenotype. Consistent with increased NRP-1 expression, cell surface binding of Sema3A increased during M2 differentiation. IFN-γ and LPS that promote classical M1 macrophage activation affected expression of NRP-1, NRP-2 and plexin A1. IFN-γ decreased NRP-1 expression and LPS suppressed NRP-2 and plexin A1 expression. Furthermore we show that Sema3A induced apoptosis in monocyte-derived macrophages, and cooperated with anti-Fas CH11 antibody to augment apoptosis. Our results suggest Sema3A plays a role in induction of apoptosis in monocyte-derived macrophages that are resistant to Fas-induced apoptosis and that its function can be modulated in inflammatory conditions. PMID:19480842

  11. Human monocyte-derived cells with individual hepatocyte characteristics: a novel tool for personalized in vitro studies.

    PubMed

    Benesic, Andreas; Rahm, Nora L; Ernst, Samuel; Gerbes, Alexander L

    2012-06-01

    Gender, ethnicity and individual differences in hepatic metabolism have major impact on individual drug response, adverse events and attrition rate during drug development. Therefore, there is an urgent need for reliable test systems based on human cells. Yet, the use of primary human hepatocytes (PHHs) is restricted by limited availability, invasive preparation and short-term stability in culture. All other cellular approaches proposed so far have major disadvantages. We investigated whether peripheral human monocytes after cultivation according to our novel protocol (monocyte-derived hepatocyte-like cells (MH cells)) can serve as an in vitro model for hepatocyte metabolism. Enzyme activities, synthesis parameters (coagulation factor VII and urea) and cytochrome (CY) P450 activities and induction were investigated. Furthermore, MH cells were compared with PHH from the same donor. Using our protocol, we could generate cells that exhibit hepatocyte-like properties: These cells show 71±9% of specific ALT activity, 41±3% of CYP3A4 activity and 65±13% of factor VII secretion when compared with PHHs. Consequently, CYP-mediated acetaminophen toxicity and drug interactions could be shown. Moreover, the investigated parameters were stable in culture over at least 4 weeks. Furthermore, MH cells retain gender-specific and donor-specific CYP activities and toxicity profiles, respectively. MH cells show quantitative and qualitative approximation to human hepatocytes concerning CYP-metabolism and toxicity. Our data support individual prediction of toxicity and CYP metabolism. MH cells are a novel tool to investigate long-term hepatic toxicity, metabolism and drug interactions. PMID:22469698

  12. Peroxisome proliferator-activated receptor gamma activators affect the maturation of human monocyte-derived dendritic cells.

    PubMed

    Gosset, P; Charbonnier, A S; Delerive, P; Fontaine, J; Staels, B; Pestel, J; Tonnel, A B; Trottein, F

    2001-10-01

    Peroxisome proliferator-activated receptor gamma (PPARgamma ), a member of the nuclear receptor superfamily, has recently been described as a modulator of macrophage functions and as an inhibitor of T cell proliferation. Here, we investigated the role of PPARgamma in dendritic cells (DC), the most potent antigen-presenting cells. We showed that PPARgamma is highly expressed in immature human monocyte-derived DC (MDDC) and that it may affect the immunostimulatory function of MDDC stimulated with lipopolysaccharide (LPS) or via CD40 ligand (CD40L). We found that the synthetic PPARgamma agonist rosiglitazone (as well as pioglitazone and troglitazone) significantly increases on LPS- and CD40L-activated MDDC, the surface expression of CD36 (by 184% and 104%, respectively) and CD86 (by 54% and 48%), whereas it reduces the synthesis of CD80 (by 42% and 42%). Moreover, activation of PPARgamma resulted in a dramatic decreased secretion of the Th1-promoting factor IL-12 in LPS- and CD40L-stimulated cells (by 47% and 62%), while the production of IL-1beta, TNF-alpha, IL-6 and IL-10 was unaffected. Finally, PPARgamma ligands down-modulate the synthesis of IFN-gamma -inducible protein-10 (recently termed as CXCL10) and RANTES (CCL5), both chemokines involved in the recruitment of Th1 lymphocytes (by 49% and 30%), but not the levels of the Th2 cell-attracting chemokines,macrophage-derived chemokine (CCL22) and thymus and activation regulated chemokine (CCL17), in mature MDDC. Taken together, our data suggest that activation of PPARgamma in human DC may have an impact in the orientation of primary and secondary immune responses by favoring type 2 responses. PMID:11592060

  13. Human monocyte-derived dendritic cells turn into foamy dendritic cells with IL-17A.

    PubMed

    Salvatore, Giulia; Bernoud-Hubac, Nathalie; Bissay, Nathalie; Debard, Cyrille; Daira, Patricia; Meugnier, Emmanuelle; Proamer, Fabienne; Hanau, Daniel; Vidal, Hubert; Aricò, Maurizio; Delprat, Christine; Mahtouk, Karène

    2015-06-01

    Interleukin 17A (IL-17A) is a proinflammatory cytokine involved in the pathogenesis of chronic inflammatory diseases. In the field of immunometabolism, we have studied the impact of IL-17A on the lipid metabolism of human in vitro-generated monocyte-derived dendritic cells (DCs). Microarrays and lipidomic analysis revealed an intense remodeling of lipid metabolism induced by IL-17A in DCs. IL-17A increased 2-12 times the amounts of phospholipids, cholesterol, triglycerides, and cholesteryl esters in DCs. Palmitic (16:0), stearic (18:0), and oleic (18:ln-9c) acid were the main fatty acid chains present in DCs. They were strongly increased in response to IL-17A while their relative proportion remained unchanged. Capture of extracellular lipids was the major mechanism of lipid droplet accumulation, visualized by electron microscopy and Oil Red O staining. Besides this foamy phenotype, IL-17A induced a mixed macrophage-DC phenotype and expression of the nuclear receptor NR1H3/liver X receptor-α, previously identified in the context of atherosclerosis as the master regulator of cholesterol homeostasis in macrophages. These IL-17A-treated DCs were as competent as untreated DCs to stimulate allogeneic naive T-cell proliferation. Following this first characterization of lipid-rich DCs, we propose to call these IL-17A-dependent cells "foamy DCs" and discuss the possible existence of foamy DCs in atherosclerosis, a metabolic and inflammatory disorder involving IL-17A. PMID:25833686

  14. Hyperbaric oxygen enhances neutrophil apoptosis and their clearance by monocyte-derived macrophages.

    PubMed

    Almzaiel, Anwar J; Billington, Richard; Smerdon, Gary; Moody, A John

    2015-08-01

    Neutrophil apoptosis and clearance by macrophages are essential for wound healing. Evidence suggests that hyperbaric oxygen (HBO) exposure may enhance neutrophil apoptosis, but HBO effects leading to neutrophil clearance by macrophages are still unclear. In the current study, bovine neutrophils and monocyte-derived macrophages (MDMΦ) were co-cultured under HBO (97.9% O2, 2.1% CO2 at 2.4 atm absolute (ATA)) (1 atm = 101.325 kPa), hyperbaric normoxia (8.8% O2 at 2.4 ATA), normobaric hyperoxia (95% O2, 5% CO2), normoxia (air), and normobaric hypoxia (5% O2, 5% CO2). Phagocytosis of fresh and 22 h aged neutrophils by MDMΦ was increased after HBO pre-treatment, assessed using flow cytometry and light microscopy. Enhanced clearance of neutrophils was accompanied by an increase in H2O2 levels following HBO pre-treatment with upregulation of IL-10 (anti-inflammatory cytokine) mRNA expression in LPS-stimulated MDMΦ that had ingested aged neutrophils. TNF-α (pro-inflammatory cytokine) gene expression did not change in LPS-stimulated MDMΦ that had ingested fresh or aged neutrophils after HBO, pressure, and hyperoxia. These findings suggest that HBO-activated MDMΦ participate in the clearance of apoptotic cells. Uptake of neutrophils by MDMΦ exposed to HBO may contribute to resolution of inflammation, because HBO induced up-regulation of IL-10 mRNA expression. PMID:26194051

  15. Constraints for monocyte-derived dendritic cell functions under inflammatory conditions.

    PubMed

    Fekete, Tünde; Szabo, Attila; Beltrame, Luca; Vivar, Nancy; Pivarcsi, Andor; Lanyi, Arpad; Cavalieri, Duccio; Rajnavölgyi, Eva; Rethi, Bence

    2012-02-01

    The activation of TLRs expressed by macrophages or DCs, in the long run, leads to persistently impaired functionality. TLR signals activate a wide range of negative feedback mechanisms; it is not known, however, which of these can lead to long-lasting tolerance for further stimulatory signals. In addition, it is not yet understood how the functionality of monocyte-derived DCs (MoDCs) is influenced in inflamed tissues by the continuous presence of stimulatory signals during their differentiation. Here we studied the role of a wide range of DC-inhibitory mechanisms in a simple and robust model of MoDC inactivation induced by early TLR signals during differentiation. We show that the activation-induced suppressor of cytokine signaling 1 (SOCS1), IL-10, STAT3, miR146a and CD150 (SLAM) molecules possessed short-term inhibitory effects on cytokine production but did not induce persistent DC inactivation. On the contrary, the LPS-induced IRAK-1 downregulation could alone lead to persistent MoDC inactivation. Studying cellular functions in line with the activation-induced negative feedback mechanisms, we show that early activation of developing MoDCs allowed only a transient cytokine production that was followed by the downregulation of effector functions and the preservation of a tissue-resident non-migratory phenotype. PMID:22057588

  16. The Salmonella virulence plasmid spv genes are required for cytopathology in human monocyte-derived macrophages.

    PubMed

    Libby, S J; Lesnick, M; Hasegawa, P; Weidenhammer, E; Guiney, D G

    2000-02-01

    The pathogenesis of serious systemic Salmonella infections is characterized by survival and proliferation of bacteria inside macrophages. Infection of human monocyte-derived macrophages in vitro with S. typhimurium or S. dublin produces cytopathology characterized by detachment of cells that contain large numbers of proliferating bacteria. This cytopathology is dependent on the expression of the bacterial spv genes, a virulence locus previously shown to markedly enhance the ability of Salmonella to produce systemic disease. After 24 h of infection, macrophage cultures contain two populations of bacteria: (i) proliferating organisms present in a detached cell fraction; and (ii) a static bacterial population in macrophages remaining attached to the culture well. Mutations in either the essential transcriptional activator SpvR or the key SpvB protein markedly reduce the cytopathic effect of Salmonella infection. The spv-dependent cytopathology in macrophages exhibits characteristics of apoptosis, with release of nucleosomes into the cytoplasm, nuclear condensation and DNA fragmentation. The current findings suggest that the mechanism of the spv effect is through induction of increased cytopathology in host macrophages. PMID:11207562

  17. Innate Allorecognition Results in Rapid Accumulation of Monocyte-Derived Dendritic Cells.

    PubMed

    Chow, Kevin V; Delconte, Rebecca B; Huntington, Nicholas D; Tarlinton, David M; Sutherland, Robyn M; Zhan, Yifan; Lew, Andrew M

    2016-09-01

    Although the mechanisms governing the innate recognition of pathogen-associated molecular patterns have been well defined, how allogeneic cellular stimuli evoke innate responses remains less so. In this article, we report that upon i.v. transfer (to avoid major iatrogenic interference), allogeneic but not syngeneic leukocytes could induce a rapid (after 1 d) accumulation of host monocyte-derived dendritic cells (moDCs) without any increase in conventional DCs. This occurred in various donor-host strain combinations, did not require MHC mismatch, and could be induced by various donor cell types including B cells, T cells, or NK cells. Using RAG(-/-)γc(-/-) and scid γc(-/-)mice with different MHC, we found that the presence of either donor or host lymphoid cells was required. Alloinduced moDC accumulation was significantly reduced when splenocytes from mice deficient in NK cells by genetic ablation were used as donors. A major component of this moDC accumulation appears to be recruitment. Our findings provide new insights into how the innate and adaptive immune system may interact during allogeneic encounters and thus transplant rejection. PMID:27474076

  18. Differential phagocytosis of Leishmania mexicana promastigotes and amastigotes by monocyte-derived dendritic cells.

    PubMed

    Argueta-Donohué, Jesús; Wilkins-Rodríguez, Arturo A; Aguirre-García, Magdalena; Gutiérrez-Kobeh, Laila

    2016-06-01

    Leishmania species are dimorphic protozoan parasites that live and replicate in the gut of sand flies as promastigotes or in mammalian hosts as amastigotes. Different immune cells, including DCs, and receptors differ in their involvement in phagocytosis of promastigotes and amastigotes and in recognition of different Leishmania species. In the case of L. mexicana, differences in phagocytosis of promastigotes and amastigotes by DCs and participation of C-type lectin receptors (CLRs) have not been established. In the present study, flow cytometry and confocal microscopy were used to investigate the phagocytosis by monocyte-derived dendritic cells (moDCs) of L. mexicana promastigotes and amastigotes in the presence or absence of immune serum during various periods of time. Blocking antibodies against mannose receptors and DC-SIGN were used to explore the participation of these receptors in the phagocytosis of L. mexicana by moDC. The major differences in interactions of L. mexicana promastigotes and amastigotes with moDC were found to occur within the first 3 hr, during which phagocytosis of promastigotes predominated as compared with opsonization of promastigotes and amastigotes. However, after 6 hr of incubation, opsonized promastigotes were preferentially phagocytosed as compared with unopsonized promastigotes and amastigotes and after 24 hr of incubation there were no differences in the phagocytosis of promastigotes and amastigotes. Finally, after 3 hr incubation, DC-SIGN was involved in the phagocytosis of promastigotes, but not of amastigotes. PMID:26399218

  19. Monocyte-derived dendritic cell subpopulations use different types of matrix metalloproteinases inhibited by GM6001.

    PubMed

    Kis-Toth, Katalin; Bacskai, Ildiko; Gogolak, Peter; Mazlo, Anett; Szatmari, Istvan; Rajnavolgyi, Eva

    2013-11-01

    Matrix metalloproteinases (MMPs) are endopeptidases with the potential to cleave extracellular matrix, support tissue renewal and regulate cell migration. Functional activities of MMPs are regulated by tissue inhibitors of MMPs (TIMPs) and disruption of the MMP-TIMP balance has pathological consequences. Here we studied the expression and secretion of MMPs and TIMPs in CD1a(-) and CD1a(+) monocyte-derived dendritic cell (DC) subpopulations. Our results showed that monocytes express TIMPs but lack MMPs, whereas upon differentiation to moDCs and in response to activation signals the expression of MMPs is increased and that of TIMPs is decreased. MMP-9 is expressed dominantly in the CD1a(-) subpopulation, while MMP-12 is preferentially expressed in CD1a(+) cells. Experiments performed with the synthetic MMP inhibitor GM6001 revealed that this drug efficiently inhibits the migration of moDCs through inactivation of MMPs. We conclude that modulation of MMP activity by GM6001 emerges as a novel approach to manipulate DC migration under inflammatory conditions. PMID:23870824

  20. Metabolic profiling during HIV-1 and HIV-2 infection of primary human monocyte-derived macrophages

    PubMed Central

    Hollenbaugh, Joseph A.; Montero, Catherine; Schinazi, Raymond F.; Munger, Joshua; Kim, Baek

    2016-01-01

    We evaluated cellular metabolism profiles of HIV-1 and HIV-2 infected primary human monocyte-derived macrophages (MDMs). First, HIV-2 GL-AN displays faster production kinetics and greater amounts of virus as compared to HIV-1s: YU-2, 89.6 and JR-CSF. Second, quantitative LC–MS/MS metabolomics analysis demonstrates very similar metabolic profiles in glycolysis and TCA cycle metabolic intermediates between HIV-1 and HIV-2 infected macrophages, with a few notable exceptions. The most striking metabolic change in MDMs infected with HIV-2 relative to HIV-1-infected MDMs was the increased levels of quinolinate, a metabolite in the tryptophan catabolism pathway that has been linked to HIV/AIDS pathogenesis. Third, both HIV-1 and HIV-2 infected MDMs showed elevated levels of ribose-5-phosphate, a key metabolic component in nucleotide biosynthesis. Finally, HIV-2 infected MDMs display increased dNTP concentrations as predicted by Vpx-mediated SAMHD1 degradation. Collectively, these data show differential metabolic changes during HIV-1 and HIV-2 infection of macrophages. PMID:26895248

  1. Immunomodulatory effects of human umbilical cord Wharton's jelly-derived mesenchymal stem cells on differentiation, maturation and endocytosis of monocyte-derived dendritic cells.

    PubMed

    Saeidi, Mohsen; Masoud, Ahmad; Shakiba, Yadollah; Hadjati, Jamshid; Mohyeddin Bonab, Mandana; Nicknam, Mohammad Hossein; Latifpour, Mostafa; Nikbin, Behrooz

    2013-03-01

    The Wharton's jelly of the umbilical cord is believed to be a source of mesenchymal stem cells (MSCs) which can be therapeutically applied in degenerative diseases.In this study, we investigated the immunomodulatory effect of umbilical cord derived-mesenchymal stem cells (UC-MSCs) and bone marrow-derived-mesenchymal stem cells (BM-MSCs) on differentiation, maturation, and endocytosis of monocyte-derived dendritic cells in a transwell culture system under laboratory conditions. Monocytes were differentiated into immature dendritic cells (iDCs) in the presence of GM-CSF and IL-4 for 6 days and then differentiated into mature dendritic cells (mDCs) in the presence of TNF-α for 2 days. In every stage of differentiation, immature and mature dendritic cells were separately co-cultured with UC-MSCs and BM-MSCs. The findings showed that UC-MSCs and BM-MSCs inhibited strongly differentiation and maturation of dendritic cells at higher dilution ratios (1:1). The BM-MSCs and UC-MSCs showed more inhibitory effect on CD1a, CD83, CD86 expression, and dendritic cell endocytic activity, respectively. On the other hand, these cells severely up-regulated CD14 marker expression. We concluded that UC-MSCs and BM-MSCs could inhibit differentiation, maturation and endocytosis in monocyte-derived DCs through the secreted factors and free of any cell-cell contacts under laboratory conditions. As DCs are believed to be the main antigen presenting cells for naïve T cells in triggering immune responses, it would be logical that their inhibitory effect on differentiation, maturation and function can decrease or modulate immune and inflammatory responses. PMID:23454777

  2. cGAS Senses Human Cytomegalovirus and Induces Type I Interferon Responses in Human Monocyte-Derived Cells.

    PubMed

    Paijo, Jennifer; Döring, Marius; Spanier, Julia; Grabski, Elena; Nooruzzaman, Mohammed; Schmidt, Tobias; Witte, Gregor; Messerle, Martin; Hornung, Veit; Kaever, Volkhard; Kalinke, Ulrich

    2016-04-01

    Human cytomegalovirus (HCMV) infections of healthy individuals are mostly unnoticed and result in viral latency. However, HCMV can also cause devastating disease, e.g., upon reactivation in immunocompromised patients. Yet, little is known about human immune cell sensing of DNA-encoded HCMV. Recent studies indicated that during viral infection the cyclic GMP/AMP synthase (cGAS) senses cytosolic DNA and catalyzes formation of the cyclic di-nucleotide cGAMP, which triggers stimulator of interferon genes (STING) and thus induces antiviral type I interferon (IFN-I) responses. We found that plasmacytoid dendritic cells (pDC) as well as monocyte-derived DC and macrophages constitutively expressed cGAS and STING. HCMV infection further induced cGAS, whereas STING expression was only moderately affected. Although pDC expressed particularly high levels of cGAS, and the cGAS/STING axis was functional down-stream of STING, as indicated by IFN-I induction upon synthetic cGAMP treatment, pDC were not susceptible to HCMV infection and mounted IFN-I responses in a TLR9-dependent manner. Conversely, HCMV infected monocyte-derived cells synthesized abundant cGAMP levels that preceded IFN-I production and that correlated with the extent of infection. CRISPR/Cas9- or siRNA-mediated cGAS ablation in monocytic THP-1 cells and primary monocyte-derived cells, respectively, impeded induction of IFN-I responses following HCMV infection. Thus, cGAS is a key sensor of HCMV for IFN-I induction in primary human monocyte-derived DC and macrophages. PMID:27058035

  3. cGAS Senses Human Cytomegalovirus and Induces Type I Interferon Responses in Human Monocyte-Derived Cells

    PubMed Central

    Paijo, Jennifer; Döring, Marius; Spanier, Julia; Grabski, Elena; Nooruzzaman, Mohammed; Schmidt, Tobias; Witte, Gregor; Messerle, Martin; Hornung, Veit; Kaever, Volkhard; Kalinke, Ulrich

    2016-01-01

    Human cytomegalovirus (HCMV) infections of healthy individuals are mostly unnoticed and result in viral latency. However, HCMV can also cause devastating disease, e.g., upon reactivation in immunocompromised patients. Yet, little is known about human immune cell sensing of DNA-encoded HCMV. Recent studies indicated that during viral infection the cyclic GMP/AMP synthase (cGAS) senses cytosolic DNA and catalyzes formation of the cyclic di-nucleotide cGAMP, which triggers stimulator of interferon genes (STING) and thus induces antiviral type I interferon (IFN-I) responses. We found that plasmacytoid dendritic cells (pDC) as well as monocyte-derived DC and macrophages constitutively expressed cGAS and STING. HCMV infection further induced cGAS, whereas STING expression was only moderately affected. Although pDC expressed particularly high levels of cGAS, and the cGAS/STING axis was functional down-stream of STING, as indicated by IFN-I induction upon synthetic cGAMP treatment, pDC were not susceptible to HCMV infection and mounted IFN-I responses in a TLR9-dependent manner. Conversely, HCMV infected monocyte-derived cells synthesized abundant cGAMP levels that preceded IFN-I production and that correlated with the extent of infection. CRISPR/Cas9- or siRNA-mediated cGAS ablation in monocytic THP-1 cells and primary monocyte-derived cells, respectively, impeded induction of IFN-I responses following HCMV infection. Thus, cGAS is a key sensor of HCMV for IFN-I induction in primary human monocyte-derived DC and macrophages. PMID:27058035

  4. Fate mapping reveals that microglia and recruited monocyte-derived macrophages are definitively distinguishable by phenotype in the retina

    PubMed Central

    O’Koren, E. G.; Mathew, R.; Saban, D. R.

    2016-01-01

    The recent paradigm shift that microglia are yolk sac-derived, not hematopoietic-derived, is reshaping our knowledge about the isolated role of microglia in CNS diseases, including degenerative conditions of the retina. However, unraveling microglial-specific functions has been hindered by phenotypic overlap of microglia with monocyte-derived macrophages. The latter are differentiated from recruited monocytes in neuroinflammation, including retina. Here we demonstrate the use of fate mapping wherein microglia and monocyte-derived cells are endogenously labeled with different fluorescent reporters. Combining this method with 12-color flow cytometry, we show that these two populations are definitively distinguishable by phenotype in retina. We prove that retinal microglia have a unique CD45lo CD11clo F4/80lo I-A/I-E− signature, conserved in the steady state and during retinal injury. The latter was observed in the widely used light-induced retinal degeneration model and corroborated in other models, including whole-body irradiation/bone-marrow transplantation. The literature contains conflicting observations about whether microglia, including in the retina, increase expression of these markers in neuroinflammation. We show that monocyte-derived macrophages have elevated expression of these surface markers, not microglia. Our resolution of such phenotypic differences may serve as a robust way to help characterize isolated roles of these cells in retinal neuroinflammation and possibly elsewhere in CNS. PMID:26856416

  5. Fate mapping reveals that microglia and recruited monocyte-derived macrophages are definitively distinguishable by phenotype in the retina.

    PubMed

    O'Koren, E G; Mathew, R; Saban, D R

    2016-01-01

    The recent paradigm shift that microglia are yolk sac-derived, not hematopoietic-derived, is reshaping our knowledge about the isolated role of microglia in CNS diseases, including degenerative conditions of the retina. However, unraveling microglial-specific functions has been hindered by phenotypic overlap of microglia with monocyte-derived macrophages. The latter are differentiated from recruited monocytes in neuroinflammation, including retina. Here we demonstrate the use of fate mapping wherein microglia and monocyte-derived cells are endogenously labeled with different fluorescent reporters. Combining this method with 12-color flow cytometry, we show that these two populations are definitively distinguishable by phenotype in retina. We prove that retinal microglia have a unique CD45(lo) CD11c(lo) F4/80(lo) I-A/I-E(-) signature, conserved in the steady state and during retinal injury. The latter was observed in the widely used light-induced retinal degeneration model and corroborated in other models, including whole-body irradiation/bone-marrow transplantation. The literature contains conflicting observations about whether microglia, including in the retina, increase expression of these markers in neuroinflammation. We show that monocyte-derived macrophages have elevated expression of these surface markers, not microglia. Our resolution of such phenotypic differences may serve as a robust way to help characterize isolated roles of these cells in retinal neuroinflammation and possibly elsewhere in CNS. PMID:26856416

  6. Bacterial Ghosts of Escherichia coli Drive Efficient Maturation of Bovine Monocyte-Derived Dendritic Cells

    PubMed Central

    Hajam, Irshad Ahmed; Dar, Pervaiz Ahmad; Appavoo, Elamurugan; Kishore, Subodh; Bhanuprakash, Veerakyathappa; Ganesh, Kondabattula

    2015-01-01

    Bacterial ghosts (BGs) are empty cell envelopes derived from Gram-negative bacteria. They not only represent a potential platform for development of novel vaccines but also provide a tool for efficient adjuvant and antigen delivery system. In the present study, we investigated the interaction between BGs of Escherichia coli (E. coli) and bovine monocyte-derived dendritic cells (MoDCs). MoDCs are highly potent antigen-presenting cells and have the potential to act as a powerful tool for manipulating the immune system. We generated bovine MoDCs in vitro from blood monocytes using E. coli expressed bovine GM-CSF and IL-4 cytokines. These MoDCs displayed typical morphology and functions similar to DCs. We further investigated the E. coli BGs to induce maturation of bovine MoDCs in comparison to E. coli lipopolysaccharide (LPS). We observed the maturation marker molecules such as MHC-II, CD80 and CD86 were induced early and at higher levels in BG stimulated MoDCs as compared to the LPS stimulated MoDCs. BG mediated stimulation induced significantly higher levels of cytokine expression in bovine MoDCs than LPS. Both pro-inflammatory (IL-12 and TNF-α) and anti-inflammatory (IL-10) cytokines were induced in MoDCs after BGs stimulation. We further analysed the effects of BGs on the bovine MoDCs in an allogenic mixed lymphocyte reaction (MLR). We found the BG-treated bovine MoDCs had significantly (p<0.05) higher capacity to stimulate allogenic T cell proliferation in MLR as compared to the LPS. Taken together, these findings demonstrate the E. coli BGs induce a strong activation and maturation of bovine MoDCs. PMID:26669936

  7. HIV Infection of Monocytes-Derived Dendritic Cells Inhibits Vγ9Vδ2 T Cells Functions

    PubMed Central

    Sacchi, Alessandra; Rinaldi, Alessandra; Tumino, Nicola; Casetti, Rita; Agrati, Chiara; Turchi, Federica; Bordoni, Veronica; Cimini, Eleonora; Martini, Federico

    2014-01-01

    DCs act as sentinel cells against incoming pathogens and represent the most potent antigen presenting cells, having the unique capability to prime naïve T cells. In addition to their role in induction of adaptive immune responses, DC are also able to activate innate cells as γδ T cells; in particular, a reciprocal crosstalk between DC and γδ T cells was demonstrated. However, whether HIV infection may alter DC-Vγ9Vδ2 T cells cross-talk was not yet described. To clarify this issue, we cultured activated Vγ9Vδ2 T cells with HIV infected monocyte derived DC (MoDC). After 5 days we evaluated MoDC phenotype, and Vγ9Vδ2 T cells activation and proliferation. In our model, Vγ9Vδ2 T cells were not able to proliferate in response to HIV-infected MoDC, although an up-regulation of CD69 was observed. Upon phosphoantigens stimulation, Vγ9Vδ2 T cells proliferation and cytokine production were inhibited when cultured with HIV-infected MoDC in a cell-contact dependent way. Moreover, HIV-infected MoDC are not able to up-regulate CD86 molecules when cultured with activated Vγ9Vδ2 T cells, compared with uninfected MoDC. Further, activated Vγ9Vδ2 T cells are not able to induce HLA DR up-regulation and CCR5 down-regulation on HIV-infected MoDC. These data indicate that HIV-infected DC alter the capacity of Vγ9Vδ2 T cells to respond to their antigens, pointing out a new mechanisms of induction of Vγ9Vδ2 T cells anergy carried out by HIV, that could contribute to immune evasion. PMID:25340508

  8. Cocaine Enhances HIV-1 Infectivity in Monocyte Derived Dendritic Cells by Suppressing microRNA-155

    PubMed Central

    Napuri, Jessica; Pilakka-Kanthikeel, Sudheesh; Raymond, Andrea; Agudelo, Marisela; Yndart-Arias, Adriana; Saxena, Shailendra K.; Nair, Madhavan

    2013-01-01

    Cocaine and other drugs of abuse increase HIV-induced immunopathogenesis; and neurobiological mechanisms of cocaine addiction implicate a key role for microRNAs (miRNAs), single-stranded non-coding RNAs that regulate gene expression and defend against viruses. In fact, HIV defends against miRNAs by actively suppressing the expression of polycistronic miRNA cluster miRNA-17/92, which encodes miRNAs including miR-20a. IFN-g production by natural killer cells is regulated by miR-155 and this miRNA is also critical to dendritic cell (DC) maturation. However, the impact of cocaine on miR-155 expression and subsequent HIV replication is unknown. We examined the impact of cocaine on two miRNAs, miR-20a and miR-155, which are integral to HIV replication, and immune activation. Using miRNA isolation and analysis, RNA interference, quantitative real time PCR, and reporter assays we explored the effects of cocaine on miR-155 and miR-20 in the context of HIV infection. Here we demonstrate using monocyte-derived dendritic cells (MDCCs) that cocaine significantly inhibited miR-155 and miR-20a expression in a dose dependent manner. Cocaine and HIV synergized to lower miR-155 and miR-20a in MDDCs by 90%. Cocaine treatment elevated LTR-mediated transcription and PU.1 levels in MDCCs. But in context of HIV infection, PU.1 was reduced in MDDCs regardless of cocaine presence. Cocaine increased DC-SIGN and and decreased CD83 expression in MDDC, respectively. Overall, we show that cocaine inhibited miR-155 and prevented maturation of MDDCs; potentially, resulting in increased susceptibility to HIV-1. Our findings could lead to the development of novel miRNA-based therapeutic strategies targeting HIV infected cocaine abusers. PMID:24391808

  9. Mesenchymal Stem Cells Derived from Human Exfoliated Deciduous Teeth (SHEDs) Induce Immune Modulatory Profile in Monocyte-Derived Dendritic Cells

    PubMed Central

    Silva, Fernando de Sá; Ramos, Rodrigo Nalio; de Almeida, Danilo Candido; Bassi, Enio Jose; Gonzales, Roberto Pereira; Miyagi, Sueli Patricia Harumi; Maranduba, Claudinéia Pereira; Sant'Anna, Osvaldo Augusto Brazil Esteves; Marques, Márcia Martins; Barbuto, José Alexandre Marzagão; Câmara, Niels Olsen Saraiva; da Costa Maranduba, Carlos Magno

    2014-01-01

    Background Mesenchymal stem cells have prominent immune modulatory properties, which may have clinical applications; however their major source, bone marrow, is of limited availability. On the other hand, mesenchymal stem cells derived from human exfoliated deciduous teeth (SHEDs) are readily accessible, but their immune regulatory properties have not been completely investigated. This study was designed, therefore, to evaluate the SHEDs influence on DCs differentiation, maturation, ability to activate T cells and to expand CD4+Foxp3+ T cells. Methodology/Principal Findings The experiments were based in cellular co-culture during differentiation and maturation of monocyte derived-DCs (moDCs), with, or not, presence of SHEDs. After co-culture with SHEDs, (moDCs) presented lower expression of BDCA-1 and CD11c, in comparison to DC cultivated without SHEDs. CD40, CD80, CD83 and CD86 levels were also decreased in mature DCs (mDCs) after co-cultivation with SHEDs. To assess the ability of SHEDs-exposed moDCs to modulate T cell responses, the former were separated from SHEDs, and co-cultured with peripheral blood lymphocytes. After 5 days, the proliferation of CD4+ and CD8+ T cells was evaluated and found to be lower than that induced by moDCs cultivated without SHEDs. In addition, an increase in the proportion of CD4+Foxp3+IL-10+ T cells was observed among cells stimulated by mature moDCs that were previously cultivated with SHEDs. Soluble factors released during co-cultures also showed a reduction in the pro-inflammatory cytokines (IL-2, TNF-α and IFN-γ), and an increase in the anti-inflammatory molecule IL-10. Conclusion/Significance This study shows that SHEDs induce an immune regulatory phenotype in moDCs cells, evidenced by changes in maturation and differentiation rates, inhibition of lymphocyte stimulation and ability to expand CD4+Foxp3+ T cells. Further characterization and validation of this phenomenon could support the use of SHEDs, directly or indirectly

  10. TLR8 agonists stimulate newly recruited monocyte-derived cells into potent APCs that enhance HBsAg immunogenicity

    PubMed Central

    Du, Jun; Wu, Zhiyuan; Ren, Shurong; Wei, Yong; Gao, Meihua; Randolph, Gwendalyn J.; Qu, Chunfeng

    2011-01-01

    We previously reported that synthetic or natural Toll-like receptor (TLR) 7/8 agonists present within dead cells enhanced cell-associated antigen presentation both in vitro and in vivo. Here, we investigated the immunopotency of different chemically synthesized TLR7/8 agonists, Resiquimod, Gardiquimod, CL075, and CL097, on HBsAg immunogenicity. These agonists stimulated inflammatory monocyte-derived cells to become potent antigen-presenting dendritic cells (DCs), which augmented HBsAg specific T cell proliferation after they were conditioned with HBsAg. The TLR8 agonist CL075 and the TLR7/8 dual agonist CL097 showed more potent effects than the TLR7 agonist. Compared with alum adjuvant, when HBsAg mixed with CL075 was injected intramuscularly into mice, more monocyte-derived DCs carried antigens into draining lymph nodes and spleens. Specific Abs, particularly IgG2a, were significantly increased, and more IL-5 and IFN-γ were produced by splenocytes and intrahepatic immunocytes in mice that received HBsAg mixed with CL075 and CL097. These results suggest that TLR8 agonists are good candidates to enhance recombinant HBsAg immunogenicity to induce specific humoral and cellular immune responses. PMID:20637759

  11. Comparison of alpha-Type-1 polarizing and standard dendritic cell cytokine cocktail for maturation of therapeutic monocyte-derived dendritic cell preparations from cancer patients.

    PubMed

    Trepiakas, Redas; Pedersen, Anders Elm; Met, Ozcan; Hansen, Morten H; Berntsen, Annika; Svane, Inge Marie

    2008-06-01

    The current "gold standard" for generation of dendritic cell (DC) used in DC-based cancer vaccine studies is maturation of monocyte-derived DCs with tumor necrosis factor-alpha (TNF-alpha)/IL-1beta/IL-6 and prostaglandin E(2) (PGE(2)). Recently, a protocol for producing so-called alpha-Type-1 polarized dendritic cells (alphaDC1) in serum-free medium was published based on maturation of monocyte-derived DCs with TNF-alpha/IL-1-beta/polyinosinic:polycytidylic acid (poly-I:C)/interferon (IFN)-alpha and IFN-gamma. This DC maturation cocktail was described to fulfill the criteria for optimal DC generation and to be superior to the standard DC (sDC) cocktail as it induced fully mature DCs with potent IL-12p70 secretion together with CCR7 expression which is necessary for priming of a TH1 response and for migration to the draining lymph node, respectively. In this study, we tested the adaptation of alphaDC1 maturation cocktail to a protocol for clinical grade DC generation from cancer patients performed in X-VIVO 15 medium. We showed that alphaDC1 in this protocol induce lower up-regulation of CD83 and several other maturation markers, co-stimulatory molecules and CCR7 together with higher up-regulation of inhibitory molecules such as PD-L1, ILT2, ILT3 as compared to sDC. Although alphaDC1 matured DCs secreted more IL-12p70 and IL-23 these DCs had lower or similar stimulatory capacity compared to sDCs when used as stimulating cells in mixed lymphocyte reaction (MLR) or for induction of autologous influenza antigen specific T lymphocytes. Thus, our observations underline that alphaDC1 maturation cannot be directly adapted to alternative protocols for DC generation. Also, this study indicates the necessity for further investigation of correlation between in vitro DC parameters and their in vivo efficacy in clinical vaccination trials. PMID:18450338

  12. The Role of Porcine Monocyte Derived Dendritic Cells (MoDC) in the Inflammation Storm Caused by Streptococcus suis Serotype 2 Infection

    PubMed Central

    Liu, Jin; Tian, Zhong-Yuan; Xiao, Yun-Cai; Wang, Xi-Liang; Jin, Mei-Lin; Shi, De-Shi

    2016-01-01

    Background Streptococcus suis is an important swine pathogen and zoonotic agent. Infection with this highly pathogenic strain can cause streptococcal toxic shock-like syndrome (STSLS), characterized by a Th-1 inflammatory cytokine storm, and a high mortality rate. Monocyte derived dendritic cells (MoDCs) are known to stimulate Th-1 cell differentiation, but the role of MoDCs in STSLS remains to be elucidated. Methodology and Findings Porcine CD14-positive monocytes, purified from peripheral blood mononuclear cells (PBMCs), were used to generate MoDCs using granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4). Highly pure MoDCs were generated, as proved by their morphology, phenotype analysis, phagocytic ability, and induction of T cells proliferation. The MoDCs were further stimulated by the virulent S. suis serotype 2 (SS2) SC19 strain which triggered a strong release of several pro-inflammatory cytokines, including IL-1β, IL-8, TNF-α, IFN-γ, and IL-12. Furthermore, the stimulated MoDCs induced CD4+ T cell differentiation towards Th-1 cells in vitro. Conclusions The results of this study indicated that the porcine MoDCs stimulated by SS2 could release high levels of Th-1 inflammatory cytokines and induce CD4+ T cell differentiation towards Th-1 cells. Hence, it is likely that porcine MoDCs play an important role in the STSLS caused by SS2. PMID:26974437

  13. Activation of peroxisome proliferator-activated receptor gamma leads to upregulation of ESE-3 expression in human monocyte-derived dendritic cells.

    PubMed

    Sprater, F; Azeem, W; Appel, S

    2014-01-01

    The transcription factor ESE-3 has been suggested to be involved in regulating the immunogenicity of human monocyte-derived dendritic cells (moDCs). While ESE-3 is not expressed in monocytes, it is upregulated during the differentiation of monocytes into dendritic cells (DCs) and highly expressed in immunogenic DCs while downregulated in tolerogenic DCs. Activation of peroxisome proliferator-activated receptor gamma (PPAR-γ) during DC development has been shown to result in a rather tolerogenic cell population. In this study, we identified eight PPAR-γ binding sites upstream of the ESE-3 gene. Activation of the PPAR-γ pathway with synthetic PPAR-γ ligands during moDC generation resulted in upregulation of ESE-3b expression on mRNA and protein level, phenotypic alterations and reduced capacity of the cells to stimulate allogeneic T cells. This could be inhibited by blocking the PPAR-γ pathway with specific antagonists. Our results suggest PPAR-γ to be involved in the regulation of ESE-3b expression during moDC development and that ESE-3 expression is not correlated with the immunogenicity of DCs. PMID:24219556

  14. Anti-CSF-1 treatment is effective to prevent carcinoma invasion induced by monocyte-derived cells but scarcely by microglia

    PubMed Central

    Rietkötter, Eva; Bleckmann, Annalen; Bayerlová, Michaela; Menck, Kerstin; Chuang, Han-Ning; Wenske, Britta; Schwartz, Hila; Erez, Neta; Binder, Claudia; Hanisch, Uwe-Karsten; Pukrop, Tobias

    2015-01-01

    The mononuclear phagocytic system is categorized in three major groups: monocyte-derived cells (MCs), dendritic cells and resident macrophages. During breast cancer progression the colony stimulating factor 1 (CSF-1) can reprogram MCs into tumor-promoting macrophages in the primary tumor. However, the effect of CSF-1 during colonization of the brain parenchyma is largely unknown. Thus, we analyzed the outcome of anti-CSF-1 treatment on the resident macrophage population of the brain, the microglia, in comparison to MCs, alone and in different in vitro co-culture models. Our results underline the addiction of MCs to CSF-1 while surprisingly, microglia were not affected. Furthermore, in contrast to the brain, the bone marrow did not express the alternative ligand, IL-34. Yet treatment with IL-34 and co-culture with carcinoma cells partially rescued the anti-CSF-1 effects on MCs. Further, MC-induced invasion was significantly reduced by anti-CSF-1 treatment while microglia-induced invasion was reduced to a lower extend. Moreover, analysis of lung and breast cancer brain metastasis revealed significant differences of CSF-1 and CSF-1R expression. Taken together, our findings demonstrate not only differences of anti-CSF-1 treatment on MCs and microglia but also in the CSF-1 receptor and ligand expression in brain and bone marrow as well as in brain metastasis. PMID:26098772

  15. Results of a phase 1 study utilizing monocyte-derived dendritic cells pulsed with tumor RNA in children and young adults with brain cancer1

    PubMed Central

    Caruso, Denise A.; Orme, Lisa M.; Neale, Alana M.; Radcliff, Fiona J.; Amor, Gerlinda M.; Maixner, Wirginia; Downie, Peter; Hassall, Timothy E.; Tang, Mimi L.K.; Ashley, David M.

    2004-01-01

    We conducted a phase 1 study of 9 pediatric patients with recurrent brain tumors using monocyte-derived dendritic cells pulsed with tumor RNA to produce antitumor vaccine (DCRNA) preparations. The objectives of this study included (1) establishing safety and feasibility and (2) measuring changes in general, antigen-specific, and tumor-specific immune responses after DCRNA. Dendritic cells were derived from freshly isolated monocytes after 7 days of culture with IL-4 and granulocyte-macrophage colony–stimulating factor, pulsed with autologous tumor RNA, and then cryopreserved. Patients received at least 3 vaccines, each consisting of an intravenous and an intra-dermal administration at biweekly intervals. The study showed that this method for producing and administering DCRNA from a single leukapheresis product was both feasible and safe in this pediatric brain tumor population. Immune function at the time of enrollment into the study was impaired in all patients tested. While humoral responses to recall antigens (diphtheria and tetanus) were intact in all patients, cellular responses to mitogen and recall antigens were below normal. Following DCRNA vaccine, 2 of 7 patients showed stable clinical disease and 1 of 7 showed a partial response. Two of 7 patients who were tested showed a tumor-specific immune response to DCRNA. This study showed that DCRNA vaccines are both safe and feasible in children with tumors of the central nervous system with a single leukapheresis. PMID:15279716

  16. Equine herpesvirus type 1 (EHV1) induces alterations in the immunophenotypic profile of equine monocyte-derived dendritic cells.

    PubMed

    Claessen, Christophe; De Lange, Valérie; Huang, Teng; Ma, Guanggang; Osterrieder, Nikolaus; Favoreel, Herman; Van de Walle, Gerlinde R

    2016-04-01

    Equine herpesvirus 1 (EHV1) is an α-herpesvirus that can infect a variety of different cells in vitro and in vivo, including dendritic cells (DC) which are essential in the immune response against EHV1. Infection of equine monocyte-derived DC (MDDC) with EHV1 induced down-regulation of major histocompatibility complex I (MHCI), CD83, CD86, CD206, CD29 and CD172a, but not of CD11a/CD18 and MHCII. This down-regulation was not mediated by the virion host-shutoff (VHS) protein or pUL49.5. Interestingly, down-regulation of CD83 and CD86 was in part mediated by pUL56. Taken together, these data indicate that EHV1 employs different and still unresolved mechanisms to induce down-regulation of several functionally important cell surface proteins on equine DC. PMID:26920348

  17. Nanoparticle based galectin-1 gene silencing, implications in methamphetamine regulation of HIV-1 infection in monocyte derived macrophages.

    PubMed

    Reynolds, Jessica L; Law, Wing Cheung; Mahajan, Supriya D; Aalinkeel, Ravikumar; Nair, Bindukumar; Sykes, Donald E; Yong, Ken-Tye; Hui, Rui; Prasad, Paras N; Schwartz, Stanley A

    2012-09-01

    Galectin-1, an adhesion molecule, is expressed in macrophages and implicated in human immunodeficiency virus (HIV-1) viral adsorption. In this study, we investigated the effects of methamphetamine on galectin-1 production in human monocyte derived macrophages (MDM) and the role of galectin-1 in methamphetamine potentiation of HIV-1 infection. Herein we show that levels of galectin-1 gene and protein expression are significantly increased by methamphetamine. Furthermore, concomitant incubation of MDM with galectin-1 and methamphetamine facilitates HIV-1 infection compared to galectin-1 alone or methamphetamine alone. We utilized a nanotechnology approach that uses gold nanorod (GNR)-galectin-1 siRNA complexes (nanoplexes) to inhibit gene expression for galectin-1. Nanoplexes significantly silenced gene expression for galectin-1 and reversed the effects of methamphetamine on galectin-1 gene expression. Moreover, the effects of methamphetamine on HIV-1 infection were attenuated in the presence of the nanoplex in MDM. PMID:22689223

  18. MicroRNA-155 modulates the interleukin-1 signaling pathway in activated human monocyte-derived dendritic cells

    PubMed Central

    Ceppi, Maurizio; Pereira, Patricia M.; Dunand-Sauthier, Isabelle; Barras, Emmanuèle; Reith, Walter; Santos, Manuel A.; Pierre, Philippe

    2009-01-01

    In response to inflammatory stimulation, dendritic cells (DCs) have a remarkable pattern of differentiation (maturation) that exhibits specific mechanisms to control immunity. Here, we show that in response to Lipopolysaccharides (LPS), several microRNAs (miRNAs) are regulated in human monocyte-derived dendritic cells. Among these miRNAs, miR-155 is highly up-regulated during maturation. Using LNA silencing combined to microarray technology, we have identified the Toll-like receptor/interleukin-1 (TLR/IL-1) inflammatory pathway as a general target of miR-155. We further demonstrate that miR-155 directly controls the level of TAB2, an important signal transduction molecule. Our observations suggest, therefore, that in mature human DCs, miR-155 is part of a negative feedback loop, which down-modulates inflammatory cytokine production in response to microbial stimuli. PMID:19193853

  19. Patient specific proteolytic activity of monocyte-derived macrophages and osteoclasts predicted with temporal kinase activation states during differentiation

    PubMed Central

    Park, Keon-Young; Li, Weiwei A.; Platt, Manu O.

    2012-01-01

    Patient-to-patient variability in disease progression continues to complicate clinical decisions of treatment regimens for cardiovascular diseases, metastatic cancers and osteoporosis. Here, we investigated if monocytes, circulating white blood cells that enter tissues and contribute to disease progression by differentiating into macrophages or osteoclasts, could be useful in understanding this variability. Monocyte-derived macrophages and osteoclasts produce cysteine cathepsins, powerful extracellular matrix proteases which have been mechanistically linked to accelerated atherosclerotic, osteoporotic, and tumor progression. We hypothesized that multivariate analysis of temporal kinase activation states during monocyte differentiation could predict cathepsin proteolytic responses of monocyte-derived macrophages and osteoclasts in a patient-specific manner. Freshly isolated primary monocytes were differentiated with M-CSF or RANKL into macrophages or osteoclasts, respectively, and phosphorylation of ERK1/2, Akt, p38 MAPK, JNK, c-jun, and IκB-α were measured at days 1, 3, 6, and 9. In parallel, cell diameters and numbers of nuclei were measured, and multiplex cathepsin zymography was used to quantify cathepsins K, L, S, and V activity from cell extracts and conditioned media. There was extensive patient-to-patient variability in temporal kinase activation states, cell morphologies, and cathepsin K, L, S, and V proteolytic activity. Partial least squares regression models trained with temporal kinase activation states successfully predicted patient-specific morphological characteristics (mean cell diameter and number of nuclei) and patient-specific cathepsin proteolytic activity with predictability as high as 95%, even with the challenge of incorporating the complex, unknown cues from individual patients’ unique genetic and biochemical backgrounds. This personalized medicine approach considers patient variability in kinase signals to predict cathepsin activity

  20. Establishing Porcine Monocyte-Derived Macrophage and Dendritic Cell Systems for Studying the Interaction with PRRSV-1

    PubMed Central

    Singleton, Helen; Graham, Simon P.; Bodman-Smith, Katherine B.; Frossard, Jean-Pierre; Steinbach, Falko

    2016-01-01

    Monocyte-derived macrophages (MoMØ) and monocyte-derived dendritic cells (MoDC) are two model systems well established in human and rodent systems that can be used to study the interaction of pathogens with host cells. Porcine reproductive and respiratory syndrome virus (PRRSV) is known to infect myeloid cells, such as macrophages (MØ) and dendritic cells (DC). Therefore, this study aimed to establish systems for the differentiation and characterization of MoMØ and MoDC for subsequent infection with PRRSV-1. M-CSF differentiated MoMØ were stimulated with activators for classical (M1) or alternative (M2) activation. GM-CSF and IL-4 generated MoDC were activated with the well established maturation cocktail containing PAMPs and cytokines. In addition, MoMØ and MoDC were treated with dexamethasone and IL-10, which are known immuno-suppressive reagents. Cells were characterized by morphology, phenotype, and function and porcine MØ subsets highlighted some divergence from described human counterparts, while MoDC, appeared more similar to mouse and human DCs. The infection with PRRSV-1 strain Lena demonstrated different replication kinetics between MoMØ and MoDC and within subsets of each cell type. While MoMØ susceptibility was significantly increased by dexamethasone and IL-10 with an accompanying increase in CD163/CD169 expression, MoDC supported only a minimal replication of PRRSV These findings underline the high variability in the susceptibility of porcine myeloid cells toward PRRSV-1 infection. PMID:27313573

  1. IL-13 REPLACES IL-4 IN DEVELOPMENT OF MONOCYTE DERIVED DENDRITIC CELLS (MODC) OF SWINE; THE INNATE IMMUNE RESPONSE OF MODC TO TOLL-LIKE RECEPTOR AGONISTS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Dendritic cells (DCs) are a critical aspect of innate immune responses in addition to initiating adaptive immunity. In vitro generation of monocyte derived dendritic cells (MoDC) by culturing cells in IL-4 and GM-CSF has been reported for multiple species including swine. However, IL-4 is not a prom...

  2. Interleukin-12 gene expression in human monocyte-derived macrophages stimulated with Mycobacterium bovis BCG: cytokine regulation and effect of NK cells.

    PubMed Central

    Matsumoto, H; Suzuki, K; Tsuyuguchi, K; Tanaka, E; Amitani, R; Maeda, A; Yamamoto, K; Sasada, M; Kuze, F

    1997-01-01

    Macrophage-derived interleukin-12 (IL-12) is essential for the activation of a protective immune response against intracellular pathogens. In this study, we examined the regulation of IL-12 mRNA expression by monocyte-derived macrophages (MDM) in response to Mycobacterium bovis BCG stimulation. A reverse transcription-PCR assay detected p40 mRNA of IL-12 at 3 h and showed a peak at 6 to 12 h with a subsequent decline. Semiquantitation of mRNA levels by competitive PCR revealed that pretreatment with gamma interferon (IFN-gamma) amplified the expression approximately 100-fold, while pretreatment with tumor necrosis factor alpha (TNF-alpha) or granulocyte-macrophage colony-stimulating factor augmented this expression about 10-fold. In contrast, pretreatment with IL-10 and IL-4 inhibited IL-12 mRNA expression. These results were further confirmed by measuring the p70 bioactive protein level in each conditioned medium by an enzyme-linked immunosorbent assay. Since IL-12 mRNA expression was weak without cytokine pretreatment and IFN-gamma strongly augmented production, we speculated that IFN-gamma might have a role in BCG stimulation of IL-12 mRNA expression. Unexpectedly, the addition of three different kinds of anti-IFN-gamma antibodies and anti-IFN-gamma receptor antibody and the coaddition of anti-TNF-alpha antibody with anti-IFN-gamma receptor antibody all failed to inhibit IL-12 mRNA expression. However, the MiniMACS method used to remove NK cells from a mononuclear cell suspension inhibited the expression of p40 mRNA but not the expression of mRNA of TNF-alpha or IL-1beta. We concluded that the coexistence of NK cells was essential for the induction of IL-12 in MDM stimulated with BCG rather than through the secretion of IFN-gamma. PMID:9353012

  3. Exposure to Δ9-Tetrahydrocannabinol Impairs the Differentiation of Human Monocyte-derived Dendritic Cells and their Capacity for T cell Activation

    PubMed Central

    Castaneda, Julie T.; Kiertscher, Sylvia M.

    2015-01-01

    The capacity for human monocytes to differentiate into antigen-presenting dendritic cells (DC) can be influenced by a number of immune modulating signals. Monocytes express intracellular cannabinoid type 1 (CB1) and 2 (CB2) receptors and we demonstrate that exposure to Δ9-tetrahydrocannabinol (THC) inhibits the forskolin-induced generation of cyclic adenosine monophosphate in a CB2-specific manner. In order to examine the potential impact of cannabinoids on the generation of monocyte-derived DC, monocytes were cultured in vitro with differentiation medium alone [containing granulocyte/macrophage-colony stimulating factor (GM-CSF) and Interleukin-4 (IL-4)] or in combination with THC. The presence of THC (0.25–1.0 μg/ml) altered key features of DC differentiation, producing a concentration-dependent decrease in surface expression of CD11c, HLA-DR and costimulatory molecules (CD40 and CD86), less effective antigen uptake, and signs of functional skewing with decreased production of IL-12 but normal levels of IL-10. When examined in a mixed leukocyte reaction, DC that had been generated in the presence of THC were poor T cell activators as evidenced by their inability to generate effector/memory T cells or to stimulate robust IFN-γ responses. Some of these effects were partially restored by exposure to exogenous IL-7 and bacterial superantigen (S. aureus Cowans strain). These studies demonstrate that human monocytes express functional cannabinoid receptors and suggest that exposure to THC can alter their differentiation into functional antigen presenting cells; an effect that may be counter-balanced by the presence of other immunoregulatory factors. The impact of cannabinoids on adaptive immune responses in individuals with frequent drug exposure remains to be determined. PMID:25614186

  4. Bordetella pertussis Proteins Dominating the Major Histocompatibility Complex Class II-Presented Epitope Repertoire in Human Monocyte-Derived Dendritic Cells

    PubMed Central

    Stenger, Rachel M.; Meiring, Hugo D.; Kuipers, Betsy; Poelen, Martien; van Gaans-van den Brink, Jacqueline A. M.; Boog, Claire J. P.; de Jong, Ad P. J. M.

    2014-01-01

    Knowledge of naturally processed Bordetella pertussis-specific T cell epitopes may help to increase our understanding of the basis of cell-mediated immune mechanisms to control this reemerging pathogen. Here, we elucidate for the first time the dominant major histocompatibility complex (MHC) class II-presented B. pertussis CD4+ T cell epitopes, expressed on human monocyte-derived dendritic cells (MDDC) after the processing of whole bacterial cells by use of a platform of immunoproteomics technology. Pertussis epitopes identified in the context of HLA-DR molecules were derived from two envelope proteins, i.e., putative periplasmic protein (PPP) and putative peptidoglycan-associated lipoprotein (PAL), and from two cytosolic proteins, i.e., 10-kDa chaperonin groES protein (groES) and adenylosuccinate synthetase (ASS). No epitopes were detectable from known virulence factors. CD4+ T cell responsiveness in healthy adults against peptide pools representing epitope regions or full proteins confirmed the immunogenicity of PAL, PPP, groES, and ASS. Elevated lymphoproliferative activity to PPP, groES, and ASS in subjects within a year after the diagnosis of symptomatic pertussis suggested immunogenic exposure to these proteins during clinical infection. The PAL-, PPP-, groES-, and ASS-specific responses were associated with secretion of functional Th1 (tumor necrosis factor alpha [TNF-α] and gamma interferon [IFN-γ]) and Th2 (interleukin 5 [IL-5] and IL-13) cytokines. Relative paucity in the natural B. pertussis epitope display of MDDC, not dominated by epitopes from known protective antigens, can interfere with the effectiveness of immune recognition of B. pertussis. A more complete understanding of hallmarks in B. pertussis-specific immunity may advance the design of novel immunological assays and prevention strategies. PMID:24599530

  5. Bordetella pertussis proteins dominating the major histocompatibility complex class II-presented epitope repertoire in human monocyte-derived dendritic cells.

    PubMed

    Stenger, Rachel M; Meiring, Hugo D; Kuipers, Betsy; Poelen, Martien; van Gaans-van den Brink, Jacqueline A M; Boog, Claire J P; de Jong, Ad P J M; van Els, Cécile A C M

    2014-05-01

    Knowledge of naturally processed Bordetella pertussis-specific T cell epitopes may help to increase our understanding of the basis of cell-mediated immune mechanisms to control this reemerging pathogen. Here, we elucidate for the first time the dominant major histocompatibility complex (MHC) class II-presented B. pertussis CD4(+) T cell epitopes, expressed on human monocyte-derived dendritic cells (MDDC) after the processing of whole bacterial cells by use of a platform of immunoproteomics technology. Pertussis epitopes identified in the context of HLA-DR molecules were derived from two envelope proteins, i.e., putative periplasmic protein (PPP) and putative peptidoglycan-associated lipoprotein (PAL), and from two cytosolic proteins, i.e., 10-kDa chaperonin groES protein (groES) and adenylosuccinate synthetase (ASS). No epitopes were detectable from known virulence factors. CD4(+) T cell responsiveness in healthy adults against peptide pools representing epitope regions or full proteins confirmed the immunogenicity of PAL, PPP, groES, and ASS. Elevated lymphoproliferative activity to PPP, groES, and ASS in subjects within a year after the diagnosis of symptomatic pertussis suggested immunogenic exposure to these proteins during clinical infection. The PAL-, PPP-, groES-, and ASS-specific responses were associated with secretion of functional Th1 (tumor necrosis factor alpha [TNF-α] and gamma interferon [IFN-γ]) and Th2 (interleukin 5 [IL-5] and IL-13) cytokines. Relative paucity in the natural B. pertussis epitope display of MDDC, not dominated by epitopes from known protective antigens, can interfere with the effectiveness of immune recognition of B. pertussis. A more complete understanding of hallmarks in B. pertussis-specific immunity may advance the design of novel immunological assays and prevention strategies. PMID:24599530

  6. Killing of Escherichia coli by Crohn's Disease Monocyte-derived Macrophages and Its Enhancement by Hydroxychloroquine and Vitamin D

    PubMed Central

    Flanagan, Paul K.; Chiewchengchol, Direkrit; Wright, Helen L.; Edwards, Steven W.; Alswied, Abdullah; Satsangi, Jack; Subramanian, Sreedhar; Rhodes, Jonathan M.

    2015-01-01

    Background: Crohn's disease (CD) is associated with defective innate immunity, including impaired neutrophil chemotaxis, and mucosal invasion by bacteria, particularly adherent and invasive Escherichia coli that replicate inside macrophage phagolysosomes. We compared CD and healthy control (HC) macrophages for their abilities to kill E. coli and generate neutrophil chemoattractants and also assessed the effects of hydroxychloroquine (HCQ) and vitamin D on killing of phagocytosed E. coli. Methods: Peripheral blood monocyte-derived macrophages from CD and HC were compared for bacterial killing and generation of neutrophil chemoattractants in response to CD-derived E. coli. Escherichia coli replication was also assessed in the presence and absence of HCQ, alone and with antibiotics, and vitamin D. Results: Monocyte-derived macrophages from patients with CD were similar to HC in allowing replication of phagocytosed CD-derived E. coli: HM605 {CD: N = 10, mean fold replication in 3 hr = 1.08 (95% confidence interval [CI], 0.39–1.78); HC: N = 9, 1.50 (95% CI, 1.02–1.97); P = 0.15} and also in generation of neutrophil chemoattractants in response to E. coli (mean fold chemotaxis relative to control: CD = 2.55 [95% CI, 2.31–2.80]; HC = 2.65 [95% CI, 2.46–2.85], P = 0.42). HCQ and 1,25 OH2-vitamin D3 both caused dose-dependent inhibition of intramacrophage E. coli replication 3-hour postinfection; HCQ: 73.9% inhibition (P < 0.001) at 1 μg/mL, accompanied by raised intraphagosomal pH, and 1,25 OH2-vitamin D3: 80.7% inhibition (P < 0.05) at 80 nM. HCQ had synergistic effects with doxycycline and ciprofloxacin. Conclusions: CD and HC macrophages perform similarly in allowing replication of phagocytosed E. coli and generating neutrophil chemoattractants. Replication of phagocytosed E. coli was substantially decreased by HCQ and vitamin D. These warrant further therapeutic trials in CD in combination with relevant antibiotics. PMID:25839777

  7. Bacillus anthracis capsule activates caspase-1 and induces interleukin-1beta release from differentiated THP-1 and human monocyte-derived dendritic cells.

    PubMed

    Cho, Min-Hee; Ahn, Hae-Jeong; Ha, Hyun-Joon; Park, Jungchan; Chun, Jeong-Hoon; Kim, Bong-Su; Oh, Hee-Bok; Rhie, Gi-Eun

    2010-01-01

    The poly-gamma-d-glutamic acid (PGA) capsule is one of the major virulence factors of Bacillus anthracis, which causes a highly lethal infection. The antiphagocytic PGA capsule disguises the bacilli from immune surveillance and allows unimpeded growth of bacilli in the host. Recently, efforts have been made to include PGA as a component of anthrax vaccine; however, the innate immune response of PGA itself has been poorly investigated. In this study, we characterized the innate immune response elicited by PGA in the human monocytic cell line THP-1, which was differentiated into macrophages with phorbol 12-myristate 13-acetate (PMA) and human monocyte-derived dendritic cells (hMoDCs). PGA capsules were isolated from the culture supernatant of either the pXO1-cured strain of B. anthracis H9401 or B. licheniformis ATCC 9945a. PGA treatment of differentiated THP-1 cells and hMoDCs led to the specific extracellular release of interleukin-1beta (IL-1beta) in a dose-dependent manner. Evaluation of IL-1beta processing by Western blotting revealed that cleaved IL-1beta increased in THP-1 cells and hMoDCs after PGA treatment. Enhanced processing of IL-1beta directly correlated with increased activation of its upstream regulator, caspase-1, also known as IL-1beta-converting enzyme (ICE). The extracellular release of IL-1beta in response to PGA was ICE dependent, since the administration of an ICE inhibitor prior to PGA treatment blocked induction of IL-1beta. These results demonstrate that B. anthracis PGA elicits IL-1beta production through activation of ICE in PMA-differentiated THP-1 cells and hMoDCs, suggesting the potential for PGA as a therapeutic target for anthrax. PMID:19737897

  8. Th2 polarization by Der p 1--pulsed monocyte-derived dendritic cells is due to the allergic status of the donors.

    PubMed

    Hammad, H; Charbonnier, A S; Duez, C; Jacquet, A; Stewart, G A; Tonnel, A B; Pestel, J

    2001-08-15

    The polarization of the immune response toward a Th2 or a Th1 profile can be mediated by dendritic cells (DCs) following antigen presentation and interaction with T cells. Costimulatory molecules such as CD80 and CD86 expressed by DCs, the polarizing cytokine environment during DC--T-cell interaction, and also the nature of the antigen are critical in the orientation of the immune response. In this study, the effect of the cysteine protease Der p 1, one of the major allergens of the house dust mite Dermatophagoides pteronyssinus, on these different parameters was evaluated comparatively on monocyte-derived DCs obtained from healthy donors, from pollen-sensitive patients, or from patients sensitive to Dermatophagoides pteronyssinus. Results showed that Der p 1 induced an increase in CD86 expression only on DCs from house dust mite--sensitive patients. This was also associated with a higher capacity to induce T-cell proliferation, a rapid increase in the production of proinflammatory cytokines, tumor necrosis factor--alpha and interleukin (IL)-1 beta, and the type 2 cytokine IL-10. No changes in the release of IL-12 p70 were induced by Der p 1. Finally, purified T cells from house dust mite-sensitive patients stimulated by autologous Der p 1--pulsed DCs preferentially produced IL-4 rather than interferon-gamma. These effects were abolished in the presence of the inactive precursor of Der p 1 (ProDer p 1). Taken together, these data suggest that DCs from house dust mite--sensitive patients, in contrast to DCs from healthy donors and from pollen-sensitive patients, exposed to Der p 1 play a pivotal role in the enhancement of the Th2 response associated with the allergic reaction developed in response to house dust mite exposure. (Blood. 2001;98:1135-1141) PMID:11493462

  9. Peroxisome Proliferator-activated Receptor γ Induces Apoptosis and Inhibits Autophagy of Human Monocyte-derived Macrophages via Induction of Cathepsin L

    PubMed Central

    Mahmood, Dler Faieeq Darweesh; Jguirim-Souissi, Imene; Khadija, El-Hadri; Blondeau, Nicolas; Diderot, Vimala; Amrani, Souliman; Slimane, Mohamed-Naceur; Syrovets, Tatiana; Simmet, Thomas; Rouis, Mustapha

    2011-01-01

    Macrophages play a pivotal role in the pathophysiology of atherosclerosis. These cells express cathepsin L (CatL), a cysteine protease that has been implicated in atherogenesis and the associated arterial remodeling. In addition, macrophages highly express peroxisome proliferator-activated receptor (PPAR) γ, a transcription factor that regulates numerous genes important for lipid and lipoprotein metabolism, for glucose homeostasis, and inflammation. Hence, PPARγ might affect macrophage function in the context of chronic inflammation such as atherogenesis. In the present study, we examined the effect of PPARγ activation on the expression of CatL in human monocyte-derived macrophages (HMDM). Activation of PPARγ by the specific agonist GW929 concentration-dependently increased the levels of CatL mRNA and protein in HMDM. By promoter analysis, we identified a functional PPAR response element-like sequence that positively regulates CatL expression. In addition, we found that PPARγ-induced CatL promotes the degradation of Bcl2 without affecting Bax protein levels. Consistently, degradation of Bcl2 could be prevented by a specific CatL inhibitor, confirming the causative role of CatL. PPARγ-induced CatL was found to decrease autophagy through reduction of beclin 1 and LC3 protein levels. The reduction of these proteins involved in autophagic cell death was antagonized either by the CatL inhibitor or by CatL knockdown. In conclusion, our data show that PPARγ can specifically induce CatL, a proatherogenic protease, in HMDM. In turn, CatL inhibits autophagy and induces apoptosis. Thus, the proatherogenic effect of CatL could be neutralized by apoptosis, a beneficial phenomenon, at least in the early stages of atherosclerosis. PMID:21700710

  10. Enterovirus-71 Virus-Like Particles Induce the Activation and Maturation of Human Monocyte-Derived Dendritic Cells through TLR4 Signaling

    PubMed Central

    Lin, Yu-Li; Hu, Yu-Chen; Liang, Cheng-Chao; Lin, Shih-Yeh; Liang, Yu-Chih; Yuan, Hui-Ping; Chiang, Bor-Luen

    2014-01-01

    Enterovirus 71 (EV71) causes seasonal epidemics of hand-foot-and-mouth disease and has a high mortality rate among young children. We recently demonstrated potent induction of the humoral and cell-mediated immune response in monkeys immunized with EV71 virus-like particles (VLPs), with a morphology resembling that of infectious EV71 virions but not containing a viral genome, which could potentially be safe as a vaccine for EV71. To elucidate the mechanisms through which EV71 VLPs induce cell-mediated immunity, we studied the immunomodulatory effects of EV71 VLPs on human monocyte-derived dendritic cells (DCs), which bind to and incorporate EV71 VLPs. DC treatment with EV71 VLPs enhanced the expression of CD80, CD86, CD83, CD40, CD54, and HLA-DR on the cell surface; increased the production of interleukin (IL)-12 p40, IL-12 p70, and IL-10 by DCs; and suppressed the capacity of DCs for endocytosis. Treatment with EV71 VLPs also enhanced the ability of DCs to stimulate naïve T cells and induced secretion of interferon (IFN)-γ by T cells and Th1 cell responses. Neutralization with antibodies against Toll-like receptor (TLR) 4 suppressed the capacity of EV71 VLPs to induce the production of IL-12 p40, IL-12 p70, and IL-10 by DCs and inhibited EV71 VLPs binding to DCs. Our study findings clarified the important role for TLR4 signaling in DCs in response to EV71 VLPs and showed that EV71 VLPs induced inhibitor of kappaB alpha (IκBα) degradation and nuclear factor of kappaB (NF-κB) activation. PMID:25360749

  11. Equine monocyte-derived macrophage cultures and their applications for infectivity and neutralization studies of equine infectious anemia virus.

    PubMed

    Raabe, M R; Issel, C J; Montelaro, R C

    1998-03-01

    Equine infectious anemia virus (EIAV) has been shown to infect cells of monocyte/macrophage lineage. These primary cells are intrinsically difficult to obtain, to purify and to culture in vitro for extended periods of time. As a result, most in vitro studies concerning this lentivirus make use of primary equine fibroblasts or transformed canine or feline cell lines. We describe methods that yield reproducibly pure cultures of equine blood monocytes from peripheral blood mononuclear cells. The in vitro differentiation of these cells into mature equine macrophage was verified using various cytochemical staining methods. The equine monocyte-derived macrophage (MDM) cultures were found to replicate cell-adapted and field strains of EIAV more efficiently than cultures of fully differentiated equine splenic macrophage. Having established reproducible and fully differentiated cultures of equine macrophage, in vitro assays of virus infectivity and serum neutralization were developed using the in vivo target cell of EIAV. These procedures, while developed for the EIAV system, should be equally useful for in vitro cultures of other macrophage-tropic pathogens of horses. PMID:9628225

  12. Leishmania donovani infection drives the priming of human monocyte-derived dendritic cells during Plasmodium falciparum co-infections.

    PubMed

    van den Bogaart, E; de Bes, H M; Balraadjsing, P P S; Mens, P F; Adams, E R; Grobusch, M P; van Die, I; Schallig, H D F H

    2015-09-01

    Functional impairment of dendritic cells (DCs) is part of a survival strategy evolved by Leishmania and Plasmodium parasites to evade host immune responses. Here, the effects of co-exposing human monocyte-derived DCs to Leishmania donovani promastigotes and Plasmodium falciparum-infected erythrocytes were investigated. Co-stimulation resulted in a dual, dose-dependent effect on DC differentiation which ranged from semi-mature cells, secreting low interleukin(-12p70 levels to a complete lack of phenotypic maturation in the presence of high parasite amounts. The effect was mainly triggered by the Leishmania parasites, as illustrated by their ability to induce semi-mature, interleukin-10-producing DCs, that poorly responded to lipopolysaccharide stimulation. Conversely, P. falciparum blood-stage forms failed to activate DCs and only slightly interfered with lipopolysaccharide effects. Stimulation with high L. donovani concentrations triggered phosphatidylserine translocation, whose onset presented after initiating the maturation impairment process. When added in combination, the two parasites could co-localize in the same DCs, confirming that the leading effects of Leishmania over Plasmodium may not be due to mutual exclusion. Altogether, these results suggest that in the presence of visceral leishmaniasis-malaria co-infections, Leishmania-driven effects may overrule the more silent response elicited by P. falciparum, shaping host immunity towards a regulatory pattern and possibly delaying disease resolution. PMID:26173941

  13. Expression of CD1a and Type-1 Polarization Are Dissociated in Human Monocyte-Derived Dendritic Cells.

    PubMed

    Mester, Brigitta; Bauer, Evelyn; Wood, Catherine E; Hermans, Ian F; Gasser, Olivier

    2015-01-01

    Ex vivo generated monocyte-derived dendritic cell (moDC)-vaccines have long been touted as promising immunotherapeutic agents for cancer treatment, although the response rate generally remains low. The reasons for this are still unclear and confounded by the diversity in manufacturing protocols that may affect moDC function. Preclinical studies have shown that the stimulatory function of dendritic cells can be improved by engaging invariant NKT cells in vivo through the presentation of the glycolipid alpha-galactosylceramide via CD1d. However, expression of CD1d on moDC has been shown to be negatively correlated with expression of CD1a, which in turn has been suggested to be a surrogate marker for IL-12 secreting type-1 polarized moDC, the preferred functional characteristics for cancer vaccines. Here we challenge this notion by showing that plasma-derived lipids drive functional levels of CD1d expression, while CD1a expression can vary considerably in these cells without being correlated with a loss of polarization or immunogenicity. PMID:26460687

  14. Microglia and monocyte-derived macrophages: functionally distinct populations that act in concert in CNS plasticity and repair

    PubMed Central

    London, Anat; Cohen, Merav; Schwartz, Michal

    2013-01-01

    Functional macrophage heterogeneity is recognized outside the central nervous system (CNS), where alternatively activated macrophages can perform immune-resolving functions. Such functional heterogeneity was largely ignored in the CNS, with respect to the resident microglia and the myeloid-derived cells recruited from the blood following injury or disease, previously defined as blood-derived microglia; both were indistinguishably perceived detrimental. Our studies have led us to view the myeloid-derived infiltrating cells as functionally distinct from the resident microglia, and accordingly, to name them monocyte-derived macrophages (mo-MΦ). Although microglia perform various maintenance and protective roles, under certain conditions when they can no longer provide protection, mo-MΦ are recruited to the damaged CNS; there, they act not as microglial replacements but rather assistant cells, providing activities that cannot be timely performed by the resident cells. Here, we focus on the functional heterogeneity of microglia/mo-MΦ, emphasizing that, as opposed to the mo-MΦ, microglia often fail to timely acquire the phenotype essential for CNS repair. PMID:23596391

  15. Monocyte-derived macrophages exhibit distinct and more restricted HIV-1 integration site repertoire than CD4(+) T cells.

    PubMed

    Kok, Yik Lim; Vongrad, Valentina; Shilaih, Mohaned; Di Giallonardo, Francesca; Kuster, Herbert; Kouyos, Roger; Günthard, Huldrych F; Metzner, Karin J

    2016-01-01

    The host genetic landscape surrounding integrated HIV-1 has an impact on the fate of the provirus. Studies analysing HIV-1 integration sites in macrophages are scarce. We studied HIV-1 integration site patterns in monocyte-derived macrophages (MDMs) and activated CD4(+) T cells derived from seven antiretroviral therapy (ART)-treated HIV-1-infected individuals whose cells were infected ex vivo with autologous HIV-1 isolated during the acute phase of infection. A total of 1,484 unique HIV-1 integration sites were analysed. Their distribution in the human genome and genetic features, and the effects of HIV-1 integrase polymorphisms on the nucleotide selection specificity at these sites were indistinguishable between the two cell types, and among HIV-1 isolates. However, the repertoires of HIV-1-hosting gene clusters overlapped to a higher extent in MDMs than in CD4(+) T cells. The frequencies of HIV-1 integration events in genes encoding HIV-1-interacting proteins were also different between the two cell types. Lastly, HIV-1-hosting genes linked to clonal expansion of latently HIV-1-infected CD4(+) T cells were over-represented in gene hotspots identified in CD4(+) T cells but not in those identified in MDMs. Taken together, the repertoire of genes targeted by HIV-1 in MDMs is distinct from and more restricted than that of CD4(+) T cells. PMID:27067385

  16. Collagen Induces Maturation of Human Monocyte-Derived Dendritic Cells by Signaling through Osteoclast-Associated Receptor

    PubMed Central

    Schultz, Heidi S.; Nitze, Louise M.; Zeuthen, Louise H.; Keller, Pernille; Gruhler, Albrecht; Pass, Jesper; Chen, Jianhe; Guo, Li; Fleetwood, Andrew J.; Hamilton, John A.; Berchtold, Martin W.

    2015-01-01

    Osteoclast-associated receptor (OSCAR) is widely expressed on human myeloid cells. Collagen types (Col)I, II, and III have been described as OSCAR ligands, and ColII peptides can induce costimulatory signaling in receptor activator for NF-κB–dependent osteoclastogenesis. In this study, we isolated collagen as an OSCAR-interacting protein from the membranes of murine osteoblasts. We have investigated a functional outcome of the OSCAR–collagen interaction in human monocyte-derived dendritic cells (DCs). OSCAR engagement by ColI/II-induced activation/maturation of DCs is characterized by upregulation of cell surface markers and secretion of cytokines. These collagen-matured DCs (Col-DCs) were efficient drivers of allogeneic and autologous naive T cell proliferation. The T cells expanded by Col-DCs secreted cytokines with no clear T cell polarization pattern. Global RNA profiling revealed that multiple proinflammatory mediators, including cytokines and cytokine receptors, components of the stable immune synapse (namely CD40, CD86, CD80, and ICAM-1), as well as components of TNF and TLR signaling, are transcriptional targets of OSCAR in DCs. Our findings indicate the existence of a novel pathway by which extracellular matrix proteins locally drive maturation of DCs during inflammatory conditions, for example, within synovial tissue of rheumatoid arthritis patients, where collagens become exposed during tissue remodeling and are thus accessible for interaction with infiltrating precursors of DCs. PMID:25725106

  17. Multidirectional interactions are bridging human NK cells with plasmacytoid and monocyte-derived dendritic cells during innate immune responses.

    PubMed

    Della Chiesa, Mariella; Romagnani, Chiara; Thiel, Andreas; Moretta, Lorenzo; Moretta, Alessandro

    2006-12-01

    During innate immune responses, natural killer (NK) cells may interact with both plasmacytoid dendritic cells (pDCs) and monocyte-derived dendritic cells (MDDCs). We show that freshly isolated NK cells promote the release by pDCs of IFN-alpha, in a CpG-dependent manner, whereas they induce IL-6 production in a CpG-independent manner. In turn pDC-derived IFN-alpha up-regulates NK-mediated killing, whereas IL-6 could promote B-cell differentiation. We also show that exposure to exogenous IL-12 or coculture with maturing MDDCs up-regulates the NK-cell-dependent IFN-alpha production by pDCs. On the other hand, NK cells cocultured with pDCs acquire the ability to kill immature MDDCs, thus favoring their editing process. Finally, we show that activated NK cells are unable to lyse pDCs because these cells display an intrinsic resistance to lysis. The exposure of pDCs to IL-3 increased their susceptibility to NK-cell cytotoxicity resulting from a de novo expression of ligands for activating NK-cell receptors, such as the DNAM-1 ligand nectin-2. Thus, different cell-to-cell interactions and various cytokines appear to control a multidirectional network between NK cells, MDDCs, and pDCs that is likely to play an important role during the early phase of innate immune responses to viral infections and to tumors. PMID:16873676

  18. Pericellular mobilization of the tissue-destructive cysteine proteinases, cathepsins B, L, and S, by human monocyte-derived macrophages.

    PubMed Central

    Reddy, V Y; Zhang, Q Y; Weiss, S J

    1995-01-01

    Human macrophages are believed to damage host tissues in chronic inflammatory disease states, but these cells have been reported to express only modest degradative activity in vitro. However, while examining the ability of human monocytes to degrade the extracellular matrix component elastin, we identified culture conditions under which the cells matured into a macrophage population that displayed a degradative phenotype hundreds of times more destructive than that previously ascribed to any other cell population. The monocyte-derived macrophages synthesized elastinolytic matrix metalloproteinases (i.e., gelatinase B and matrilysin) as well as cysteine proteinases (i.e., cathepsins B, L, and S), but only the cathepsins were detected in the extracellular milieu as fully processed, mature enzymes by either vital fluorescence or active-site labeling. Consistent with these observations, macrophage-mediated elastinolytic activity was not affected by matrix metalloproteinase inhibitors but could be almost completely abrogated by inhibiting cathepsins L and S. These data demonstrate that human macrophages mobilize cysteine proteinases to arm themselves with a powerful effector mechanism that can participate in the pathophysiologic remodeling of the extracellular matrix. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 PMID:7731994

  19. Monocyte-derived macrophages exhibit distinct and more restricted HIV-1 integration site repertoire than CD4+ T cells

    PubMed Central

    Kok, Yik Lim; Vongrad, Valentina; Shilaih, Mohaned; Di Giallonardo, Francesca; Kuster, Herbert; Kouyos, Roger; Günthard, Huldrych F.; Metzner, Karin J.

    2016-01-01

    The host genetic landscape surrounding integrated HIV-1 has an impact on the fate of the provirus. Studies analysing HIV-1 integration sites in macrophages are scarce. We studied HIV-1 integration site patterns in monocyte-derived macrophages (MDMs) and activated CD4+ T cells derived from seven antiretroviral therapy (ART)-treated HIV-1-infected individuals whose cells were infected ex vivo with autologous HIV-1 isolated during the acute phase of infection. A total of 1,484 unique HIV-1 integration sites were analysed. Their distribution in the human genome and genetic features, and the effects of HIV-1 integrase polymorphisms on the nucleotide selection specificity at these sites were indistinguishable between the two cell types, and among HIV-1 isolates. However, the repertoires of HIV-1-hosting gene clusters overlapped to a higher extent in MDMs than in CD4+ T cells. The frequencies of HIV-1 integration events in genes encoding HIV-1-interacting proteins were also different between the two cell types. Lastly, HIV-1-hosting genes linked to clonal expansion of latently HIV-1-infected CD4+ T cells were over-represented in gene hotspots identified in CD4+ T cells but not in those identified in MDMs. Taken together, the repertoire of genes targeted by HIV-1 in MDMs is distinct from and more restricted than that of CD4+ T cells. PMID:27067385

  20. Comparison of small interfering RNA (siRNA) delivery into bovine monocyte-derived macrophages by transfection and electroporation

    PubMed Central

    Jensen, Kirsty; Anderson, Jennifer A.; Glass, Elizabeth J.

    2014-01-01

    The manipulation of the RNA interference pathway using small interfering RNA (siRNA) has become the most frequently used gene silencing method. However, siRNA delivery into primary cells, especially primary macrophages, is often considered challenging. Here we report the investigation of the suitability of two methodologies: transient transfection and electroporation, to deliver siRNA targeted against the putative immunomodulatory gene Mediterranean fever (MEFV) into primary bovine monocyte-derived macrophages (bMDM). Eleven commercial transfection reagents were investigated with variable results with respect to siRNA uptake, target gene knock-down, cell toxicity and type I interferon (IFN) response induction. Three transfection reagents: Lipofectamine 2000, Lipofectamine RNAiMAX and DharmaFECT 3, were found to consistently give the best results. However, all the transfection reagents tested induced an IFN response in the absence of siRNA, which could be minimized by reducing the transfection reagent incubation period. In addition, optimized siRNA delivery into bMDM by electroporation achieved comparable levels of target gene knock-down as transient transfection, without a detectable IFN response, but with higher levels of cell toxicity. The optimized transient transfection and electroporation methodologies may provide a starting point for optimizing siRNA delivery into macrophages derived from other species or other cells considered difficult to investigate with siRNA. PMID:24598124

  1. Exposure to Bacillus anthracis Capsule Results in Suppression of Human Monocyte-Derived Dendritic Cells

    PubMed Central

    Chabot, Donald J.; Bozue, Joel A.; Tobery, Steven A.; West, Michael W.; Moody, Krishna; Yang, De; Oppenheim, Joost J.

    2014-01-01

    The antiphagocytic capsule of Bacillus anthracis is a major virulence factor. We hypothesized that it may also mediate virulence through inhibition of the host's immune responses. During an infection, the capsule exists attached to the bacterial surface but also free in the host tissues. We sought to examine the impact of free capsule by assessing its effects on human monocytes and immature dendritic cells (iDCs). Human monocytes were differentiated into iDCs by interleukin-4 (IL-4) and granulocyte-macrophage colony-stimulating factor (GM-CSF) over 7 days in the presence of capsule derived from wild-type encapsulated B. anthracis Ames (WT) or a control preparation from an isogenic B. anthracis Ames strain that produces only 2% of the capsule of the WT (capA mutant). WT capsule consistently induced release of IL-8 and IL-6 while the capA mutant control preparation elicited either no response or only a minimal release of IL-8. iDCs that were differentiated in the presence of WT capsule had increased side scatter (SSC), a measure of cellular complexity, when assessed by flow cytometry. iDCs differentiated in the presence of WT capsule also matured less well in response to subsequent B. anthracis peptidoglycan (Ba PGN) exposure, with reduced upregulation of the chemokine receptor CCR7, reduced CCR7-dependent chemotaxis, and reduced release of certain cytokines. Exposure of naive differentiated control iDCs to WT capsule did not alter cell surface marker expression but did elicit IL-8. These results indicate that free capsule may contribute to the pathogenesis of anthrax by suppressing the responses of immune cells and interfering with the maturation of iDCs. PMID:24891109

  2. Responsiveness of human monocyte-derived dendritic cells to thimerosal and mercury derivatives

    SciTech Connect

    Migdal, C.; Tailhardat, M.; Courtellemont, P.; Haftek, M.; Serres, M.

    2010-07-15

    Several cases of skin sensitization have been reported following the application of thimerosal, which is composed of ethyl mercury and thiosalicylic acid (TSA). However, few in vitro studies have been carried out on human dendritic cells (DCs) which play an essential role in the initiation of allergic contact dermatitis. The aim of the present study was to identify the effect of thimerosal and other mercury compounds on human DCs. To address this purpose, DCs derived from monocytes (mono-DCs) were used. Data show that thimerosal and mercury derivatives induced DC activation, as monitored by CD86 and HLA-DR overexpression associated with the secretion of tumor necrosis factor {alpha} and interleukin 8, similarly to lipopolysaccharide and the sensitizers, 1-chloro-2,4-dinitrobenzene (DNCB) and nickel sulfate, which were used as positive controls. In contrast, TSA, the non-mercury part of thimerosal, as well as dichloronitrobenzene, a DNCB negative control, and the irritant, sodium dodecyl sulfate, had no effect. Moreover, oxidative stress, monitored by ROS induction and depolarization of the mitochondrial membrane potential, was induced by thimerosal and mercury compounds, as well as DNCB, in comparison with hydrogen peroxide, used as a positive control. The role of thiol oxidation in the initiation of mono-DC activation was confirmed by a pre-treatment with N-acetyl-L-cysteine which strongly decreased chemical-induced CD86 overexpression. These data are in agreement with several clinical observations of the high relevance of thimerosal in patch-test reactions and prove that human mono-DCs are useful in vitro tools for determining the allergenic potency of chemicals.

  3. Expression and regulation of Schlafen (SLFN) family members in primary human monocytes, monocyte-derived dendritic cells and T cells

    PubMed Central

    Puck, Alexander; Aigner, Regina; Modak, Madhura; Cejka, Petra; Blaas, Dieter; Stöckl, Johannes

    2015-01-01

    Schlafen (SLFN/Slfn) family members have been investigated for their involvement in fundamental cellular processes including growth regulation, differentiation and control of viral replication. However, most research has been focused on the characterization of Slfns within the murine system or in human cell lines. Since little is known about SLFNs in primary human immune cells, we set out to analyze the expression and regulation of the six human SLFN genes in monocytes, monocyte-derived dendritic cells (moDCs) and T cells. Comparison of SLFN gene expression across these three cell types showed high mRNA expression of SLFN11 in monocytes and moDCs and high SLFN5 expression in T cells, indicating functional importance within these cell types. Differentiation of monocytes to moDCs leads to the gradual upregulation of SLFN12L and SLFN13 while SLFN12 levels were decreased by differentiation stimuli. Stimulation of moDCs via human rhinovirus, lipopolysaccharide, or IFN-α lead to strong upregulation of SLFN gene expression, while peptidoglycan poorly stimulated regulation of both SLFNs and the classical interferon-stimulated gene MxA. T cell activation was found to downregulate the expression of SLFN5, SLFN12 and SLFN12L, which was reversible upon addition of exogenous IFN-α. In conclusion, we demonstrate, that SLFN gene upregulation is mainly dependent on autocrine type I interferon signaling in primary human immune cells. Rapid decrease of SLFN expression levels following T cell receptor stimulation indicates a role of SLFNs in the regulation of human T cell quiescence. PMID:26623250

  4. Triggering of B7h by the ICOS modulates maturation and migration of monocyte-derived dendritic cells.

    PubMed

    Occhipinti, Sergio; Dianzani, Chiara; Chiocchetti, Annalisa; Boggio, Elena; Clemente, Nausicaa; Gigliotti, Casimiro Luca; Soluri, Maria Felicia; Minelli, Rosalba; Fantozzi, Roberto; Yagi, Jungi; Rojo, Josè Maria; Sblattero, Daniele; Giovarelli, Mirella; Dianzani, Umberto

    2013-02-01

    B7h, expressed by several cell types, binds ICOS expressed by activated T cells. We have previously shown that B7h triggering by ICOS-Fc inhibits human endothelial cell adhesiveness. This work investigated the effect of ICOS-Fc on human monocyte-derived dendritic cells (DCs). We found that DCs matured with LPS in the presence of ICOS-Fc (mDCs(ICOS)) produced greater amounts of IL-23 and IL-10, and promoted a higher secretion of IL-17A and IL-17F in MLCs than did those DCs matured with LPS alone (mDCs). Moreover, mDCs(ICOS) pulsed with the keyhole limpet hemocyanin Ag during the maturation phase were better stimulators of Ag-specific MHC class I-, but not class II-restricted T cells than mDCs. This was probably due to promotion of cross-presentation because it was not detected when the Flu-MA(58-66) Ag was directly loaded on already matured DCs and mDCs(ICOS). Finally, ICOS-Fc inhibited the adhesion of both immature DCs and mDCs to vascular and lymphoid endothelial cells, their migratory activity, and the expression of the Rac-1 activator β-Pix involved in cell motility. These data suggest that B7h stimulation modulates DC function with effects on their maturation and recruitment into tissues. This opens a novel view on the use of interactors of the ICOS:B7h system as immunomodulatory drugs. PMID:23275603

  5. Extracellular nucleotides regulate CCL20 release from human primary airway epithelial cells, monocytes and monocyte-derived dendritic cells.

    PubMed

    Marcet, Brice; Horckmans, Michael; Libert, Frédérick; Hassid, Sergio; Boeynaems, Jean-Marie; Communi, Didier

    2007-06-01

    Extracellular nucleotides regulate ion transport and mucociliary clearance in human airway epithelial cells (HAECs) via the activation of P2 receptors, especially P2Y(2). Therefore, P2Y(2) receptor agonists represent potential pharmacotherapeutic agents to treat cystic fibrosis (CF). Nucleotides also modulate inflammatory properties of immune cells like dendritic cells (DCs), which play an important role in mucosal immunity. Using DNA-microarray experiments, quantitative RT-PCR and cytokine measurements, we show here that UTP up-regulated approximately 2- to 3-fold the antimicrobial chemokine CCL20 expression and release in primary HAECs cultured on permeable supports at an air-liquid interface (ALI). Both P2Y(2) (ATPgammaS, UTP, INS365) and P2Y(6) (UDP, INS48823) agonists increased CCL20 release. UTP-induced CCL20 release was insensitive to NF-kappaB pathway inhibitors but sensitive to inhibitors of ERK1/2 and p38/MAPK pathways. Furthermore, UTP had no effect on interleukin-(IL)-8 release and reduced the release of both CCL20 and IL-8 induced by TNF-alpha and LPS. Accordingly, UTP reduced the capacity of basolateral supernatants of HAECs treated with TNF-alpha or LPS to induce the chemoattraction of both CD4(+) T lymphocytes and neutrophils. In addition, we show that, in monocyte-derived DCs, ATPgammaS, and UDP but not UTP/INS365-stimulated CCL20 release. Likewise, UDP but not ATPgammaS was also able to increase CCL20 release from monocytes. Pharmacological experiments suggested an involvement of P2Y(11) or P2Y(6) receptors through NF-kappaB, ERK1/2, and p38/MAPK pathways. Altogether, our data demonstrate that nucleotides may modulate chemokine release and leukocyte recruitment in inflamed airways by acting on both epithelial and immune cells. Our results could be relevant for further clinical investigations in CF. PMID:17295217

  6. Alcohol and Cannabinoids Differentially Affect HIV Infection and Function of Human Monocyte-Derived Dendritic Cells (MDDC)

    PubMed Central

    Agudelo, Marisela; Figueroa, Gloria; Yndart, Adriana; Casteleiro, Gianna; Muñoz, Karla; Samikkannu, Thangavel; Atluri, Venkata; Nair, Madhavan P.

    2015-01-01

    During human immunodeficiency virus (HIV) infection, alcohol has been known to induce inflammation while cannabinoids have been shown to have an anti-inflammatory role. For instance cannabinoids have been shown to reduce susceptibility to HIV-1 infection and attenuate HIV replication in macrophages. Recently, we demonstrated that alcohol induces cannabinoid receptors and regulates cytokine production by monocyte-derived dendritic cells (MDDC). However, the ability of alcohol and cannabinoids to alter MDDC function during HIV infection has not been clearly elucidated yet. In order to study the potential impact of alcohol and cannabinoids on differentiated MDDC infected with HIV, monocytes were cultured for 7 days with GM-CSF and IL-4, differentiated MDDC were infected with HIV-1Ba-L and treated with EtOH (0.1 and 0.2%), THC (5 and 10 μM), or JWH-015 (5 and 10 μM) for 4–7 days. HIV infection of MDDC was confirmed by p24 and Long Terminal Repeats (LTR) estimation. MDDC endocytosis assay and cytokine array profiles were measured to investigate the effects of HIV and substances of abuse on MDDC function. Our results show the HIV + EtOH treated MDDC had the highest levels of p24 production and expression when compared with the HIV positive controls and the cannabinoid treated cells. Although both cannabinoids, THC and JWH-015 had lower levels of p24 production and expression, the HIV + JWH-015 treated MDDC had the lowest levels of p24 when compared to the HIV + THC treated cells. In addition, MDDC endocytic function and cytokine production were also differentially altered after alcohol and cannabinoid treatments. Our results show a differential effect of alcohol and cannabinoids, which may provide insights into the divergent inflammatory role of alcohol and cannabinoids to modulate MDDC function in the context of HIV infection. PMID:26733986

  7. Cooperation between Monocyte-Derived Cells and Lymphoid Cells in the Acute Response to a Bacterial Lung Pathogen

    PubMed Central

    Brown, Andrew S.; Yang, Chao; Fung, Ka Yee; Bachem, Annabell; Bourges, Dorothée; Bedoui, Sammy; Hartland, Elizabeth L.; van Driel, Ian R.

    2016-01-01

    Legionella pneumophila is the causative agent of Legionnaires’ disease, a potentially fatal lung infection. Alveolar macrophages support intracellular replication of L. pneumophila, however the contributions of other immune cell types to bacterial killing during infection are unclear. Here, we used recently described methods to characterise the major inflammatory cells in lung after acute respiratory infection of mice with L. pneumophila. We observed that the numbers of alveolar macrophages rapidly decreased after infection coincident with a rapid infiltration of the lung by monocyte-derived cells (MC), which, together with neutrophils, became the dominant inflammatory cells associated with the bacteria. Using mice in which the ability of MC to infiltrate tissues is impaired it was found that MC were required for bacterial clearance and were the major source of IL12. IL12 was needed to induce IFNγ production by lymphoid cells including NK cells, memory T cells, NKT cells and γδ T cells. Memory T cells that produced IFNγ appeared to be circulating effector/memory T cells that infiltrated the lung after infection. IFNγ production by memory T cells was stimulated in an antigen-independent fashion and could effectively clear bacteria from the lung indicating that memory T cells are an important contributor to innate bacterial defence. We also determined that a major function of IFNγ was to stimulate bactericidal activity of MC. On the other hand, neutrophils did not require IFNγ to kill bacteria and alveolar macrophages remained poorly bactericidal even in the presence of IFNγ. This work has revealed a cooperative innate immune circuit between lymphoid cells and MC that combats acute L. pneumophila infection and defines a specific role for IFNγ in anti-bacterial immunity. PMID:27300652

  8. The identification of markers of macrophage differentiation in PMA-stimulated THP-1 cells and monocyte-derived macrophages.

    PubMed

    Daigneault, Marc; Preston, Julie A; Marriott, Helen M; Whyte, Moira K B; Dockrell, David H

    2010-01-01

    Differentiated macrophages are the resident tissue phagocytes and sentinel cells of the innate immune response. The phenotype of mature tissue macrophages represents the composite of environmental and differentiation-dependent imprinting. Phorbol-12-myristate-13-acetate (PMA) and 1,25-dihydroxyvitamin D3 (VD(3)) are stimuli commonly used to induce macrophage differentiation in monocytic cell lines but the extent of differentiation in comparison to primary tissue macrophages is unclear. We have compared the phenotype of the promonocytic THP-1 cell line after various protocols of differentiation utilising VD(3) and PMA in comparison to primary human monocytes or monocyte-derived macrophages (MDM). Both stimuli induced changes in cell morphology indicative of differentiation but neither showed differentiation comparable to MDM. In contrast, PMA treatment followed by 5 days resting in culture without PMA (PMAr) increased cytoplasmic to nuclear ratio, increased mitochondrial and lysosomal numbers and altered differentiation-dependent cell surface markers in a pattern similar to MDM. Moreover, PMAr cells showed relative resistance to apoptotic stimuli and maintained levels of the differentiation-dependent anti-apoptotic protein Mcl-1 similar to MDM. PMAr cells retained a high phagocytic capacity for latex beads, and expressed a cytokine profile that resembled MDM in response to TLR ligands, in particular with marked TLR2 responses. Moreover, both MDM and PMAr retained marked plasticity to stimulus-directed polarization. These findings suggest a modified PMA differentiation protocol can enhance macrophage differentiation of THP-1 cells and identify increased numbers of mitochondria and lysosomes, resistance to apoptosis and the potency of TLR2 responses as important discriminators of the level of macrophage differentiation for transformed cells. PMID:20084270

  9. Human monocyte-derived dendritic cells turn into foamy dendritic cells with IL-17A1[S

    PubMed Central

    Salvatore, Giulia; Bernoud-Hubac, Nathalie; Bissay, Nathalie; Debard, Cyrille; Daira, Patricia; Meugnier, Emmanuelle; Proamer, Fabienne; Hanau, Daniel; Vidal, Hubert; Aricò, Maurizio; Delprat, Christine; Mahtouk, Karène

    2015-01-01

    Interleukin 17A (IL-17A) is a proinflammatory cytokine involved in the pathogenesis of chronic inflammatory diseases. In the field of immunometabolism, we have studied the impact of IL-17A on the lipid metabolism of human in vitro-generated monocyte-derived dendritic cells (DCs). Microarrays and lipidomic analysis revealed an intense remodeling of lipid metabolism induced by IL-17A in DCs. IL-17A increased 2–12 times the amounts of phospholipids, cholesterol, triglycerides, and cholesteryl esters in DCs. Palmitic (16:0), stearic (18:0), and oleic (18:ln-9c) acid were the main fatty acid chains present in DCs. They were strongly increased in response to IL-17A while their relative proportion remained unchanged. Capture of extracellular lipids was the major mechanism of lipid droplet accumulation, visualized by electron microscopy and Oil Red O staining. Besides this foamy phenotype, IL-17A induced a mixed macrophage-DC phenotype and expression of the nuclear receptor NR1H3/liver X receptor-α, previously identified in the context of atherosclerosis as the master regulator of cholesterol homeostasis in macrophages. These IL-17A-treated DCs were as competent as untreated DCs to stimulate allogeneic naive T-cell proliferation. Following this first characterization of lipid-rich DCs, we propose to call these IL-17A-dependent cells “foamy DCs” and discuss the possible existence of foamy DCs in atherosclerosis, a metabolic and inflammatory disorder involving IL-17A. PMID:25833686

  10. Role of cytomegalovirus on the maturation and function of monocyte derived dendritic cells of liver transplant patients

    PubMed Central

    Karimi, Mohammad Hossein; Shariat, Afsoon; Yaghobi, Ramin; Mokhtariazad, Talat; Moazzeni, Seyed Mohammad

    2016-01-01

    AIM: To study the impact of association between cytomegalovirus (CMV) pathogenesis with dendritic cell (DC) maturation and function was evaluated in CMV reactivated liver transplanted patients in comparing with non-reactivated ones, and healthy controls. METHODS: Monocyte derived dendritic cells (MoDCs) was generated from collected ethylenediaminetetraacetic acid-treated blood samples from patient groups and controls. In these groups, expression rates and mean fluorescent intensity of DC markers were evaluated using flowcytometry technique. Secretion of cytokines including: interleukin (IL)-6, IL-12 and IL-23 were determined using enzyme-linked immunosorbent assay methods. The gene expression of toll-like receptor 2 (TLR2), TLR4 and IL-23 were analyzed using in-house real-time polymerase chain reaction protocols. RESULTS: Results have been shown significant decreases in: Expression rates of MoDC markers including CD83, CD1a and human leukocyte antigen DR (HLA-DR), the mean fluorescence intensitys for CD1a and HLA-DR, and secretion of IL-12 in CMV reactivated compared with non-reactivated liver transplanted patients. On the other hand, significant increases have been shown in the secretions of IL-6 and IL-23 and gene expression levels of TLR2, TLR4 and IL-23 from MoDCs in CMV reactivated compared with non-reactivated liver transplanted recipients. CONCLUSION: DC functional defects in CMV reactivated recipients, such as decrease in expression of DC maturation markers, increase in secretion of proinflammatory cytokines, and TLRs can emphasize on the importance of CMV infectivity in development of liver rejection in transplanted patients. PMID:27358779

  11. Gene Expression Profiling of Human Monocyte-derived Dendritic Cells – Searching for Molecular Regulators of Tolerogenicity

    PubMed Central

    Schinnerling, Katina; García-González, Paulina; Aguillón, Juan Carlos

    2015-01-01

    The ability of dendritic cells (DCs) to initiate and modulate antigen-specific immune responses has made them attractive targets for immunotherapy. Since DC research in humans is limited by the scarcity of DC populations in the blood circulation, most of our knowledge about DC biology and function has been obtained in vitro from monocyte-derived DCs (moDCs), which can be readily generated in sufficient numbers and are able to differentiate into distinct functional subsets depending on the nature of stimulus. In particular, moDCs with tolerogenic properties (tolDCs) possess great therapeutic potential for the treatment of autoimmune diseases. Several protocols have been developed to generate tolDCs in vitro, able to reinstruct auto-reactive T cells and to promote regulatory cells. While ligands and soluble mediators, by which DCs shape immune responses, have been vastly studied, the intracellular pathways and transcriptional regulators that govern tolDC differentiation and function are poorly understood. Whole-genome microarrays and proteomics provide useful strategies to dissect the complex molecular processes that promote tolerogenicity. Only few attempts have been made to understand tolDC biology through a global view on “omics” profiles. So far, the identification of a common regulator of tolerogenicity has been hampered by the fact that each protocol, used for tolDC generation, targets distinct signaling pathways. Here, we review the progress in understanding the transcriptional regulation of moDC differentiation, with a special focus on tolDCs, and highlight candidate molecules that might be associated with DC tolerogenicity. PMID:26539195

  12. The effect of bovine viral diarrhea virus (BVDV) strains on bovine monocyte-derived dendritic cells (Mo-DC) phenotype and capacity to produce BVDV

    PubMed Central

    2014-01-01

    Background Dendritic cells (DC) are important antigen presentation cells that monitor, process, and present antigen to T cells. Viruses that infect DC can have a devastating impact on the immune system. In this study, the ability of bovine viral diarrhea virus (BVDV) to replicate and produce infectious virus in monocyte-derived dendritic cells (Mo-DC) and monocytes was studied. The study also examined the effect of BVDV infection on Mo-DC expression of cell surface markers, including MHCI, MHCII, and CD86, which are critical for DC function in immune response. Methods Peripheral blood mononuclear cells (PBMCs) were isolated from bovine blood through gradient centrifugation. The adherent monocytes were isolated from PBMCs and differentiated into Mo-DC using bovine recombinant interleukin-4 (IL-4) and granulocyte-macrophage colony-stimulating factor (GMCSF). To determine the effect of BVDV on Mo-DC, four strains of BVDV were used including the severe acute non-cytopathic (ncp) BVDV2a-1373; moderate acute ncp BVDV2a 28508-5; and a homologous virus pair [i.e., cytopathic (cp) BVDV1b TGAC and ncp BVDV1b TGAN]. The Cooper strain of bovine herpesvirus 1 (BHV1) was used as the control virus. Mo-DC were infected with one of the BVDV strains or BHV-1 and were subsequently examined for virus replication, virus production, and the effect on MHCI, MHCII, and CD86 expression. Results The ability of monocytes to produce infectious virus reduced as monocytes differentiated to Mo-DC, and was completely lost at 120 hours of maturation. Interestingly, viral RNA increased throughout the course of infection in Mo-DC, and the viral non-structural (NS5A) and envelope (E2) proteins were expressed. The ncp strains of BVDV down-regulated while cp strain up-regulated the expression of the MHCI, MHCII, and CD86 on Mo-DC. Conclusions The study revealed that the ability of Mo-DC to produce infectious virus was reduced with its differentiation from monocytes to Mo-DC. The inability to produce

  13. The TLR7/8 ligand resiquimod targets monocyte-derived dendritic cell differentiation via TLR8 and augments functional dendritic cell generation.

    PubMed

    Hackstein, Holger; Knoche, Angela; Nockher, Angelika; Poeling, Jochen; Kubin, Thomas; Jurk, Marion; Vollmer, Jörg; Bein, Gregor

    2011-01-01

    Imidazoquinolone compounds, such as resiquimod are Toll-like receptor (TLR) 7/8 ligands representing novel immune response modifiers undergoing clinical testing. Resiquimod has been reported to modulate conventional human monocyte-derived DC (moDC) differentiation, but the role of TLR7 and TLR8 is unclear. We directly dissected the TLR7- and TLR8-dependency by employing selective TLR7 ligands and resiquimod-coculture experiments with inhibitory oligonucleotides (iODN) suppressing TLR7, TLR7+8 or TLR7+8+9. Selective TLR7 ligands did not affect conventional moDC differentiation as analyzed by CD14/CD1a expression. iODN experiments confirmed that resiquimod's effects during DC differentiation were antagonized only with TLR8 iODNs. Direct comparison of resiquimod DC with TLR7- and control-DC revealed significantly higher T-cell costimulatory molecule and MHC class II expression. Resiquimod DC promoted significantly stronger allogeneic T-cell proliferation and stronger naïve CD4(+) T-cell proliferation. These results indicate the relevance of TLR8 for human monocyte-derived DC differentiation and maturation and may be relevant for clinical trials employing resiquimod. PMID:21889130

  14. In vitro suppression of immune responses using monocyte-derived tolerogenic dendritic cells from patients with primary Sjögren's syndrome

    PubMed Central

    2013-01-01

    Introduction Therapeutic vaccination with antigen-specific tolerogenic dendritic cells (tolDC) might become a future option of individualized therapy for patients with autoimmune diseases. In this study, we tested the possibility of generating monocyte-derived tolDC from patients with primary Sjögren's syndrome (pSS). We analyzed phenotype, cytokine production and ability to suppress Ro/La-specific immune responses. Methods Monocyte-derived tolDC from patients with pSS were generated in the presence of dexamethasone, vitamin D3 and lipopolysaccharide (DexVD3 DC). The phenotype was analyzed by flow cytometry and the cytokine profile was investigated using a 25-plex Luminex assay and ELISA. The capacity to both stimulate Ro/La-specific T cells and suppress this response was evaluated by autologous mixed lymphocyte reaction (MLR). Results DC generated from patients with pSS had a similar phenotype and cytokine profile to those from healthy controls. DexVD3 DC from pSS patients induced little antigen-specific T cell proliferation, but DexVD3 DC-primed lymphocytes successfully suppressed Ro/La-specific T cell responses. Conclusions DexVD3 DC presenting Ro/La antigens might be a promising new therapeutic option for patients with pSS. PMID:24025795

  15. Serum opsonin ficolin-A enhances host-fungal interactions and modulates cytokine expression from human monocyte-derived macrophages and neutrophils following Aspergillus fumigatus challenge.

    PubMed

    Bidula, Stefan; Sexton, Darren W; Schelenz, Silke

    2016-04-01

    Invasive aspergillosis is a devastating invasive fungal disease associated with a high mortality rate in the immunocompromised, such as leukaemia patients, transplant patients and those with HIV/AIDS. The rodent serum orthologue of human L-ficolin, ficolin-A, can bind to and opsonize Aspergillus fumigatus, the pathogen that causes invasive aspergillosis, and may participate in fungal defence. Using human monocyte-derived macrophages and neutrophils isolated from healthy donors, we investigated conidial association and fungal viability by flow cytometry and microscopy. Additionally, cytokine production was measured via cytometric bead arrays. Ficolin-A opsonization was observed to significantly enhance association of conidia, while also inhibiting hyphal growth and contributing to increased fungal killing following incubation with monocyte-derived macrophages and neutrophils. Additionally, ficolin-A opsonization was capable of manifesting a decrease in IL-8, IL-1β, IL-6, IL-10 and TNF-α production from MDM and IL-1β, IL-6 and TNF-α from neutrophils 24 h post-infection. In conclusion, rodent ficolin-A is functionally comparable to human L-ficolin and is capable of modulating the innate immune response to A. fumigatus, down-regulating cytokine production and could play an important role in airway immunity. PMID:26337048

  16. Maturation of the viral core enhances the fusion of HIV-1 particles with primary human T cells and monocyte-derived macrophages

    SciTech Connect

    Jiang Jiyang; Aiken, Christopher . E-mail: chris.aiken@vanderbilt.edu

    2006-03-15

    HIV-1 infection requires fusion of viral and cellular membranes in a reaction catalyzed by the viral envelope proteins gp120 and gp41. We recently reported that efficient HIV-1 particle fusion with target cells is linked to maturation of the viral core by an activity of the gp41 cytoplasmic domain. Here, we show that maturation enhances the fusion of a variety of recombinant viruses bearing primary and laboratory-adapted Env proteins with primary human CD4{sup +} T cells. Overall, HIV-1 fusion was more dependent on maturation for viruses bearing X4-tropic envelope proteins than for R5-tropic viruses. Fusion of HIV-1 with monocyte-derived macrophages was also dependent on particle maturation. We conclude that the ability to couple fusion to particle maturation is a common feature of HIV-1 Env proteins and may play an important role during HIV-1 replication in vivo.

  17. Modern Lineages of Mycobacterium tuberculosis Exhibit Lineage-Specific Patterns of Growth and Cytokine Induction in Human Monocyte-Derived Macrophages

    PubMed Central

    Sarkar, Rajesh; Lenders, Laura; Wilkinson, Katalin A.; Wilkinson, Robert J.; Nicol, Mark P.

    2012-01-01

    Background Strains of Mycobacterium tuberculosis vary in virulence. Strains that have caused outbreaks in the United States and United Kingdom have been shown to subvert the innate immune response as a potential immune evasion mechanism. There is, however, little information available as to whether these patterns of immune subversion are features of individual strains or characteristic of broad clonal lineages of M. tuberculosis. Methods Strains from two major modern lineages (lineage 2 [East-Asian] and lineage 4 [Euro-American]) circulating in the Western Cape in South Africa as well as a comparator modern lineage (lineage 3 [CAS/Delhi]) were identified. We assessed two virulence associated characteristics: mycobacterial growth (in liquid broth and monocyte derived macrophages) and early pro-inflammatory cytokine induction. Results In liquid culture, Lineage 4 strains grew more rapidly and reached higher plateau levels than other strains (lineage 4 vs. lineage 2 p = 0.0024; lineage 4 vs. lineage 3 p = 0.0005). Lineage 3 strains were characterized by low and early plateau levels, while lineage 2 strains showed an intermediate growth phenotype. In monocyte-derived macrophages, lineage 2 strains grew faster than lineage 3 strains (p<0.01) with lineage 4 strains having an intermediate phenotype. Lineage 2 strains induced the lowest levels of pro-inflammatory TNF and IL-12p40 as compared to other lineages (lineage 2: median TNF 362 pg/ml, IL-12p40 91 pg/ml; lineage 3: median TNF 1818 pg/ml, IL-12p40 123 pg/ml; lineage 4: median TNF 1207 pg/ml, IL-12p40 205 pg/ml;). In contrast, lineage 4 strains induced high levels of IL-12p40 and intermediate level of TNF. Lineage 3 strains induced high levels of TNF and intermediate levels of IL-12p40. Conclusions Strains of M. tuberculosis from the three major modern strain lineages possess distinct patterns of growth and cytokine induction. Rapid growth and immune subversion may be key characteristics to the success of

  18. Single point mutations in the helicase domain of the NS3 protein enhance dengue virus replicative capacity in human monocyte-derived dendritic cells and circumvent the type I interferon response.

    PubMed

    Silveira, G F; Strottmann, D M; de Borba, L; Mansur, D S; Zanchin, N I T; Bordignon, J; dos Santos, C N Duarte

    2016-01-01

    Dengue is the most prevalent arboviral disease worldwide. The outcome of the infection is determined by the interplay of viral and host factors. In the present study, we evaluated the cellular response of human monocyte-derived DCs (mdDCs) infected with recombinant dengue virus type 1 (DV1) strains carrying a single point mutation in the NS3hel protein (L435S or L480S). Both mutated viruses infect and replicate more efficiently and produce more viral progeny in infected mdDCs compared with the parental, non-mutated virus (vBACDV1). Additionally, global gene expression analysis using cDNA microarrays revealed that the mutated DVs induce the up-regulation of the interferon (IFN) signalling and pattern recognition receptor (PRR) canonical pathways in mdDCs. Pronounced production of type I IFN were detected specifically in mdDCs infected with DV1-NS3hel-mutated virus compared with mdDCs infected with the parental virus. In addition, we showed that the type I IFN produced by mdDCs is able to reduce DV1 infection rates, suggesting that cytokine function is effective but not sufficient to mediate viral clearance of DV1-NS3hel-mutated strains. Our results demonstrate that single point mutations in subdomain 2 have important implications for adenosine triphosphatase (ATPase) activity of DV1-NS3hel. Although a direct functional connection between the increased ATPase activity and viral replication still requires further studies, these mutations speed up viral RNA replication and are sufficient to enhance viral replicative capacity in human primary cell infection and circumvent type I IFN activity. This information may have particular relevance for attenuated vaccine protocols designed for DV. PMID:26340409

  19. Inhibition of TNF-α, IL-1α, and IL-1β by Pretreatment of Human Monocyte-Derived Macrophages with Menaquinone-7 and Cell Activation with TLR Agonists In Vitro.

    PubMed

    Pan, Min-Hsiung; Maresz, Katarzyna; Lee, Pei-Sheng; Wu, Jia-Ching; Ho, Chi-Tang; Popko, Janusz; Mehta, Dilip S; Stohs, Sidney J; Badmaev, Vladimir

    2016-07-01

    Circulatory markers of low-grade inflammation such as tumor necrosis factor-alpha (TNF-α), interleukin-1 alpha (IL-1α), and interleukin-1 beta (IL-1β) positively correlate with endothelial damage, atheroma formation, cardiovascular disease, and aging. The natural vitamin K2-menaquinone-7 (MK-7) added to the cell culture of human monocyte-derived macrophages (hMDMs) at the same time as toll-like receptor (TLR) agonists did not influence the production of TNF-α. When the cells were pretreated up to 6 h with MK-7 before treatment with TLR agonists, MK-7 did not inhibit significantly the production of TNF-α after the TLR activation. However, 30 h pretreatment of hMDMs with at least 10 μM of MK-7 effectively and dose dependently inhibited the proinflammatory function of hMDMs. Pretreatment of hMDMs with 10 μM of MK-7 for 30 h resulted in 20% inhibition of TNF-α production after lipopolysaccharide (LPS) activation (P < .05) and 43% inhibition after macrophage-activating lipopeptide (MALP) activation (P < .001). Pathogen-associated molecular pattern (PMPP) activation was inhibited by 20% with MK-7 pretreatment; however, this inhibition was not statistically significant. The 30 h pretreatment of a THP-1-differentiated monocyte cell line with MK-7 resulted in a dose-dependent downregulation of TNFα, IL-1α, and IL-1β gene expression as evaluated by RNA semiquantitative reverse transcription polymerase chain reaction (RT-PCR). MK-7 is able to modulate immune and inflammatory reactions in the dose-response inhibition of TNF-α, IL-1α, and IL-1β gene expression and protein production by the healthy hMDMs in vitro. PMID:27200471

  20. Leishmania mexicana promastigotes down regulate JNK and p-38 MAPK activation: Role in the inhibition of camptothecin-induced apoptosis of monocyte-derived dendritic cells.

    PubMed

    Rodríguez-González, Jorge; Wilkins-Rodríguez, Arturo; Argueta-Donohué, Jesús; Aguirre-García, Magdalena; Gutiérrez-Kobeh, Laila

    2016-04-01

    Dendritic cells (DC) are one of the principal host cells of the obligate intracellular parasite Leishmania. Inhibition of host cell apoptosis is a strategy employed by multiple pathogens to ensure their survival in the infected cell. We have previously shown that the infection of monocyte-derived dendritic cells (moDC) with Leishmania mexicana inhibits campthotecin-induced apoptosis. Nevertheless, the mechanisms involved in the inhibition of apoptosis of dendritic cells by Leishmania have not been established. Mitogen-activated protein kinases (MAPK) are key participants in the process of apoptosis and different species of Leishmania have been shown to regulate these kinases. In the present study, we analyzed the effect of L. mexicana promastigotes in the activation of JNK and p38 MAP kinase and their participation in the inhibition of apoptosis. The infection of moDC with L. mexicana promastigotes diminished significantly the phosphorylation of the MAP kinases JNK and p38. The inhibition of both kinases diminished DNA fragmentation, but in a major extent was the reduction of DNA fragmentation when JNK was inhibited. The capacity of L. mexicana promastigotes to diminish MAP kinases activation is probably one of the strategies employed to delay apoptosis induction in the infected moDC and may have implications for Leishmania pathogenesis by favoring the invasion of its host and the persistence of the parasite in the infected cells. PMID:26777406

  1. Paradigm Shift in Dendritic Cell-Based Immunotherapy: From in vitro Generated Monocyte-Derived DCs to Naturally Circulating DC Subsets

    PubMed Central

    Wimmers, Florian; Schreibelt, Gerty; Sköld, Annette E.; Figdor, Carl G.; De Vries, I. Jolanda M.

    2014-01-01

    Dendritic cell (DC)-based immunotherapy employs the patients’ immune system to fight neoplastic lesions spread over the entire body. This makes it an important therapy option for patients suffering from metastatic melanoma, which is often resistant to chemotherapy. However, conventional cellular vaccination approaches, based on monocyte-derived DCs (moDCs), only achieved modest response rates despite continued optimization of various vaccination parameters. In addition, the generation of moDCs requires extensive ex vivo culturing conceivably hampering the immunogenicity of the vaccine. Recent studies, thus, focused on vaccines that make use of primary DCs. Though rare in the blood, these naturally circulating DCs can be readily isolated and activated thereby circumventing lengthy ex vivo culture periods. The first clinical trials not only showed increased survival rates but also the induction of diversified anti-cancer immune responses. Upcoming treatment paradigms aim to include several primary DC subsets in a single vaccine as pre-clinical studies identified synergistic effects between various antigen-presenting cells. PMID:24782868

  2. Comparative analysis of the early transcriptome of Brucella abortus - infected monocyte-derived macrophages from cattle naturally resistant or susceptible to brucellosis

    PubMed Central

    Rossetti, C.A.; Galindo, C.L.; Everts, R.E.; Lewin, H.A.; Garner, H.R.; Adams, L.G.

    2010-01-01

    Brucellosis is a worldwide zoonotic infectious disease that has a significant economic impact on animal production and human public health. We characterized the gene expression profile of B. abortus-infected monocyte-derived macrophages (MDMs) from naïve cattle naturally resistant (R) or susceptible (S) to brucellosis using a cDNA microarray technology. Our data indicate that 1) B. abortus induced a slightly increased genome activation in R MDMs and a down-regulated transcriptome in S MDMs, during the onset of infection, 2) R MDMs had the ability to mount a type 1 immune response against B. abortus infection which was impaired in S cells, and 3) the host cell activity was not altered after 12h post-B. abortus infection in R MDMs while the cell cycle was largely arrested in infected S MDMs at 12h p.i. These results contribute to understand of how host responses may be manipulated to prevent infection by brucellae. PMID:20932540

  3. High Intracellular Concentrations of Posaconazole Do Not Impact on Functional Capacities of Human Polymorphonuclear Neutrophils and Monocyte-Derived Macrophages In Vitro.

    PubMed

    Farowski, Fedja; Cornely, Oliver A; Hartmann, Pia

    2016-06-01

    Posaconazole is a commonly used antifungal for the prophylaxis and treatment of invasive fungal infections. We previously demonstrated that the intracellular concentration of posaconazole in peripheral blood mononuclear cells (PBMCs) and polymorphonuclear neutrophils (PMNs) was greatly increased compared to the plasma concentration. As these professional phagocytes are crucial to combat fungal infections, we set out to investigate if and how, beneficial or deleterious, this high loading of intracellular posaconazole impacts the functional capacities of these cells. Here, we show that high intracellular concentrations of posaconazole do not significantly impact PMN and monocyte-derived macrophage function in vitro In particular, killing capacity and cytoskeletal features of PMN, such as migration, are not affected, indicating that these cells serve as vehicles for posaconazole to the site of infection. Moreover, since posaconazole as such slowed the germination of Aspergillus fumigatus conidia, infected neutrophils released less reactive oxygen species (ROS). Based on these findings, we propose that the delivery of posaconazole by neutrophils to the site of Aspergillus species infection warrants control of the pathogen and preservation of tissue integrity at the same time. PMID:27021317

  4. Toll-like receptor 3 (TLR3): a new marker of canine monocytes-derived dendritic cells (cMo-DC).

    PubMed

    Bonnefont-Rebeix, Catherine; Marchal, Thierry; Bernaud, Janine; Pin, Jean-Jacques; Leroux, Caroline; Lebecque, Serge; Chabanne, Luc; Rigal, Dominique

    2007-07-15

    Toll-like receptors (TLRs) are a family of functionally important receptors for recognition of pathogen-associated molecular pattern (PAMP) since they trigger the pro-inflammatory response and upregulation of costimulatory molecules, linking the rapid innate response to adaptative immunity. In human leukocytes, TLR3 has been found to be specifically expressed in dendritic cells (DC). This study examined the expression of TLR3 in canine monocytes-derived DC (cMo-DC) and PBMC using three new anti-TLR3 mAbs (619F7, 722E2 and 713E4 clones). The non-adherent cMo-DC generated after culture in canine IL-4 plus canine GM-CSF were labelled with the three anti-TLR3 clones by flow cytometry, with a strong expression shown for 619F7 and 722E2 clones. By contrast, TLR3 expression was low to moderate in canine monocytes and lymphocytes. These results were confirmed by Western blot using 619F7 and 722E2 clones and several polypeptide bands were observed, suggesting a possible cleavage of TLR3 molecule or different glycosylation states. In addition, TLR3 was detectable in immunocytochemistry by using 722E2 clone. In conclusion, this first approach to study canine TLR3 protein expression shows that three anti-TLR3 clones detect canine TLR3 and can be used to better characterize canine DC and the immune system of dogs. PMID:17521746

  5. Elevated level of pro inflammatory cytokine and chemokine expression in chicken bone marrow and monocyte derived dendritic cells following LPS induced maturation.

    PubMed

    Kalaiyarasu, Semmannan; Bhatia, Sandeep; Mishra, Niranjan; Sood, Richa; Kumar, Manoj; SenthilKumar, D; Bhat, Sushant; Dass Prakash, M

    2016-09-01

    The study was designed to characterize and compare chicken bone marrow and peripheral blood monocyte derived dendritic cells (chBM-DC and chMoDC) and to evaluate inflammatory cytokine and chemokine alterations in response upon LPS stimulation. Typical morphology was observed in DCs from 48h of culture using recombinant chicken GM-CSF and IL-4. Maturation of DCs with LPS (1μg/ml) showed significant up regulation of mRNA of surface markers (CD40, CD80, CD83, CD86, MHC-II and DC-LAMP (CD208)), pro-inflammatory cytokines (IL-1β, IL-6, TNF-α (LITAF)), iNOS, chemokine CXCli2 and TLRs4 and 15. Basal level of TLR1 mRNA expression was higher followed by TLR15 in both DCs irrespective of their origin. Expression of iNOS and CXCLi2 mRNA in mature DCs of both origins were higher than other surface molecules and cytokines studied. Hence, its level of expression can also be used as an additional maturation marker for LPS induced chicken dendritic cell maturation along with CD83 and CD40. LPS matured DCs of both origins upregulated IL-12 and IFN-γ. Based on CD40 and CD83 mRNA expression, it was observed that LPS induced the maturation in both DCs, but chMoDCs responded better in expression of surface markers and inflammatory mediator genes. PMID:27344111

  6. Gallic Acid Is the Major Active Component of Cortex Moutan in Inhibiting Immune Maturation of Human Monocyte-Derived Dendritic Cells.

    PubMed

    Chan, Ben Chung Lap; Li, Long Fei; Hu, Shui Qing; Wat, Elaine; Wong, Eric Chun Wai; Zhang, Vanilla Xin; Lau, Clara Bik San; Wong, Chun Kwok; Hon, Kam Lun Ellis; Hui, Patrick Chi Leung; Leung, Ping Chung

    2015-01-01

    Atopic dermatitis (AD) is a widely prevalent and chronically relapsing inflammatory skin disease. Penta Herbs Formula (PHF) is efficacious in improving the quality of life and reducing topical corticosteroid used in children with AD and one of the active herbs it contains is Cortex Moutan. Recent studies showed that altered functions of dendritic cells (DC) were observed in atopic individuals, suggesting that DC might play a major role in the generation and maintenance of inflammation by their production of pro-inflammatory cytokines. Hence, the aims of the present study were to identify the major active component(s) of Cortex Moutan, which might inhibit DC functions and to investigate their possible interactions with conventional corticosteroid on inhibiting the development of DC from monocytes. Monocyte-derived dendritic cells (moDC) culture model coupled with the high-speed counter-current chromatography (HSCCC), high pressure liquid chromatography (HPLC) and Liquid Chromatography-Mass Spectrometry (LCMS) analyses were used. Gallic acid was the major active component from Cortex Moutan which could dose dependently inhibit interleukin (IL)-12 p40 and the functional cluster of differentiation (CD) surface markers CD40, CD80, CD83 and CD86 expression from cytokine cocktail-activated moDC. Gallic acid could also lower the concentration of hydrocortisone required to inhibit the activation of DC. PMID:26378505

  7. Prophylactic vaccines are potent activators of monocyte-derived dendritic cells and drive effective anti-tumor responses in melanoma patients at the cost of toxicity.

    PubMed

    Bol, Kalijn F; Aarntzen, Erik H J G; Pots, Jeanette M; Olde Nordkamp, Michel A M; van de Rakt, Mandy W M M; Scharenborg, Nicole M; de Boer, Annemiek J; van Oorschot, Tom G M; Croockewit, Sandra A J; Blokx, Willeke A M; Oyen, Wim J G; Boerman, Otto C; Mus, Roel D M; van Rossum, Michelle M; van der Graaf, Chantal A A; Punt, Cornelis J A; Adema, Gosse J; Figdor, Carl G; de Vries, I Jolanda M; Schreibelt, Gerty

    2016-03-01

    Dendritic cell (DC)-based immunotherapy is explored worldwide in cancer patients, predominantly with DC matured with pro-inflammatory cytokines and prostaglandin E2. We studied the safety and efficacy of vaccination with monocyte-derived DC matured with a cocktail of prophylactic vaccines that contain clinical-grade Toll-like receptor ligands (BCG, Typhim, Act-HIB) and prostaglandin E2 (VAC-DC). Stage III and IV melanoma patients were vaccinated via intranodal injection (12 patients) or combined intradermal/intravenous injection (16 patients) with VAC-DC loaded with keyhole limpet hemocyanin (KLH) and mRNA encoding tumor antigens gp100 and tyrosinase. Tumor antigen-specific T cell responses were monitored in blood and skin-test infiltrating-lymphocyte cultures. Almost all patients mounted prophylactic vaccine- or KLH-specific immune responses. Both after intranodal injection and after intradermal/intravenous injection, tumor antigen-specific immune responses were detected, which coincide with longer overall survival in stage IV melanoma patients. VAC-DC induce local and systemic CTC grade 2 and 3 toxicity, which is most likely caused by BCG in the maturation cocktail. The side effects were self-limiting or resolved upon a short period of systemic steroid therapy. We conclude that VAC-DC can induce functional tumor-specific responses. Unfortunately, toxicity observed after vaccination precludes the general application of VAC-DC, since in DC maturated with prophylactic vaccines BCG appears to be essential in the maturation cocktail. PMID:26861670

  8. Nonopsonic phagocytosis of nonmucoid Pseudomonas aeruginosa by human neutrophils and monocyte-derived macrophages is correlated with bacterial piliation and hydrophobicity.

    PubMed Central

    Speert, D P; Loh, B A; Cabral, D A; Salit, I E

    1986-01-01

    We have shown previously that some strains of Pseudomonas aeruginosa from patients with cystic fibrosis are phagocytized by human polymorphonuclear leukocytes in the absence of serum opsonins. The purpose of this study was to identify the bacterial features which render certain strains susceptible to nonopsonic phagocytosis. Three strains were phagocytized by human neutrophils and monocyte-derived macrophages, and two were not, as determined by luminol-enhanced chemiluminescence, visual inspection of stained smears, and bactericidal assay. Strains that were phagocytized formed pellicles when grown in static broth, but the phagocytosis-resistant strains did not. The phagocytosis-susceptible strains were more heavily piliated and more hydrophobic than the resistant strains. Bacteria exposed to heat (60 degrees C) or UV irradiation were depiliated, as assessed by electron microscopy, and rendered resistant to phagocytosis. When P. aeruginosa was grown on agar, it was piliated, hydrophobic, and susceptible to nonopsonic phagocytosis, but when grown to stationary phase in shaken broth, it was nonpiliated, less hydrophobic, and resistant to phagocytosis. It appears that nonopsonic phagocytosis of certain P. aeruginosa strains by human polymorphonuclear leukocytes and macrophages is facilitated by hydrophobic interactions which may be determined in part by pili. PMID:2873104

  9. Human monocyte-derived macrophages infected with virulent Shigella flexneri in vitro undergo a rapid cytolytic event similar to oncosis but not apoptosis.

    PubMed Central

    Fernandez-Prada, C M; Hoover, D L; Tall, B D; Venkatesan, M M

    1997-01-01

    Infection of human monocyte-derived macrophages in vitro with virulent Shigella flexneri resulted in cell death which involved rupture of the plasma membrane, cell swelling, disintegration of ultrastructure, and generalized karyolysis. These features bore resemblance to oncosis and are in striking contrast to previously described observations of mouse macrophages, where a similar infection by virulent Shigella resulted in cell death by apoptosis. Cell death by oncosis in human macrophages was confirmed by lactate dehydrogenase release, light microscopy, electron microscopy, terminal deoxynucleotidyltransferase end labeling of DNA ends, DNA fragmentation assays, and fluorescence-activated cell sorter analysis of propidium-labeled nuclei. Thus, the phenomena of cell death induced by virulent Shigella in human and mouse macrophages reflect different biochemical pathways. Interleukin-1beta (IL-1beta) was released in culture supernatants of human macrophages infected with virulent bacteria. Inhibition with IL-1beta-converting enzyme inhibitors indicated, however, that this release occurred as a passive event of cell lysis. The patterns of intracellular survival of Shigella strains within human and mouse macrophages reflect differences that exist not only between Shigella serotypes but also between the two different macrophage cell types. PMID:9119491

  10. Middle East respiratory syndrome coronavirus shows poor replication but significant induction of antiviral responses in human monocyte-derived macrophages and dendritic cells.

    PubMed

    Tynell, Janne; Westenius, Veera; Rönkkö, Esa; Munster, Vincent J; Melén, Krister; Österlund, Pamela; Julkunen, Ilkka

    2016-02-01

    In this study we assessed the ability of Middle East respiratory syndrome coronavirus (MERS-CoV) to replicate and induce innate immunity in human monocyte-derived macrophages and dendritic cells (MDDCs), and compared it with severe acute respiratory syndrome coronavirus (SARS-CoV). Assessments of viral protein and RNA levels in infected cells showed that both viruses were impaired in their ability to replicate in these cells. Some induction of IFN-λ1, CXCL10 and MxA mRNAs in both macrophages and MDDCs was seen in response to MERS-CoV infection, but almost no such induction was observed in response to SARS-CoV infection. ELISA and Western blot assays showed clear production of CXCL10 and MxA in MERS-CoV-infected macrophages and MDDCs. Our data suggest that SARS-CoV and MERS-CoV replicate poorly in human macrophages and MDDCs, but MERS-CoV is nonetheless capable of inducing a readily detectable host innate immune response. Our results highlight a clear difference between the viruses in activating host innate immune responses in macrophages and MDDCs, which may contribute to the pathogenesis of infection. PMID:26602089

  11. Analysis of histone post translational modifications in primary monocyte derived macrophages using reverse phase×reverse phase chromatography in conjunction with porous graphitic carbon stationary phase.

    PubMed

    Minshull, Thomas C; Cole, Joby; Dockrell, David H; Read, Robert C; Dickman, Mark J

    2016-07-01

    A two dimensional-liquid chromatography (2D-LC) based approach was developed for the identification and quantification of histone post translational modifications in conjunction with mass spectrometry analysis. Using a bottom-up strategy, offline 2D-LC was developed using reverse phase chromatography. A porous graphitic carbon stationary phase in the first dimension and a C18 stationary phase in the second dimension interfaced with mass spectrometry was used to analyse global levels of histone post translational modifications in human primary monocyte-derived macrophages. The results demonstrated that 84 different histone peptide proteoforms, with modifications at 18 different sites including combinatorial marks were identified, representing an increase in the identification of histone peptides by 65% and 51% compared to two different 1D-LC approaches on the same mass spectrometer. The use of the porous graphitic stationary phase in the first dimension resulted in efficient separation of histone peptides across the gradient, with good resolution and is orthogonal to the online C18 reverse phase chromatography. Overall, more histone peptides were identified using the 2D-LC approach compared to conventional 1D-LC approaches. In addition, a bioinformatic pipeline was developed in-house to enable the high throughput efficient and accurate quantification of fractionated histone peptides. The automation of a section of the downstream analysis pipeline increased the throughput of the 2D-LC-MS/MS approach for the quantification of histone post translational modifications. PMID:27260198

  12. Evaluation of an optimized protocol using human peripheral blood monocyte derived dendritic cells for the in vitro detection of sensitizers: Results of a ring study in five laboratories.

    PubMed

    Reuter, Hendrik; Gerlach, Silke; Spieker, Jochem; Ryan, Cindy; Bauch, Caroline; Mangez, Claire; Winkler, Petra; Landsiedel, Robert; Templier, Marie; Mignot, Aurelien; Gerberick, Frank; Wenck, Horst; Aeby, Pierre; Schepky, Andreas

    2015-08-01

    Allergic contact dermatitis is a delayed T-cell mediated allergic response associated with relevant social and economic impacts. Animal experiments (e.g. the local lymph node assay) are still supplying most of the data used to assess the sensitization potential of new chemicals. However, the 7th amendment to the EU Cosmetic Directive have introduced a testing ban for cosmetic ingredients after March 2013. We have developed and optimized a stable and reproducible in vitro protocol based on human peripheral blood monocyte derived dendritic cells to assess the sensitization potential of chemicals. To evaluate the transferability and the predictivity of this PBMDCs based test protocol, a ring study was organized with five laboratories using seven chemicals with a known sensitization potential (one none-sensitizer and six sensitizers, including one pro-hapten). The results indicated that this optimized test protocol could be successfully transferred to all participating laboratories and allowed a correct assessment of the sensitization potential of the tested set of chemicals. This should allow a wider acceptance of PBMDCs as a reliable test system for the detection of human skin sensitizers and the inclusion of this protocol in the toolbox of in vitro methods for the evaluation of the skin sensitization potential of chemicals. PMID:25868915

  13. Monocyte-Derived Dendritic Cells from Patients with Dermatophytosis Restrict the Growth of Trichophyton rubrum and Induce CD4-T Cell Activation

    PubMed Central

    Santiago, Karla; Bomfim, Gisele Facholi; Criado, Paulo Ricardo; Almeida, Sandro Rogerio

    2014-01-01

    Dermatophytes are the most common agents of superficial mycoses that are caused by mold fungi. Trichophyton rubrum is the most common pathogen causing dermatophytosis. The immunology of dermatophytosis is currently poorly understood. Recently, our group investigated the interaction of T. rubrum conidia with peritoneal mouse macrophages. We found that macrophages phagocytose T. rubrum conidia resulted in a down-modulation of class II major histocompatibility complex (MHC) antigens and in the expression of co-stimulatory molecules. Furthermore, it induced the production of IL-10, and T. rubrum conidia differentiated into hyphae that grew and killed the macrophages after 8 hrs of culture. This work demonstrated that dendritic cells (DCs) and macrophages, from patients or normal individuals, avidly interact with pathogenic fungus T. rubrum. The dermatophyte has two major receptors on human monocyte-derived DC: DC-SIGN and mannose receptor. In contrast macrophage has only mannose receptor that participates in the phagocytosis or bound process. Another striking aspect of this study is that unlike macrophages that permit rapid growth of T. rubrum, human DC inhibited the growth and induces Th activation. The ability of DC from patients to interact and kill T. rubrum and to present Ags to T cells suggests that DC may play an important role in the host response to T. rubrum infection by coordinating the development of cellular immune response. PMID:25372145

  14. FABP4-mediated homocysteine-induced cholesterol accumulation in THP-1 monocyte-derived macrophages and the potential epigenetic mechanism.

    PubMed

    Jiang, Yideng; Ma, Shengchao; Zhang, Huiping; Yang, Xiaoling; Lu, Guan Jun; Zhang, Hui; He, Yangyang; Kong, Fanqi; Yang, Anning; Xu, Hua; Zhang, Minghao; Jiao, Yun; Li, Guizhong; Cao, Jun; Jia, Yuexia; Jin, Shaoju; Wei, Jun; Shi, Yingkang

    2016-07-01

    Hyperhomocysteinemia (HHcy) is an independent risk factor for the development of atherosclerosis (AS), according to overwhelming number of clinical and epidemiological studies. However, the underlying pathogenic molecular mechanisms by which HHcy promotes AS remain to be fully elucidated. Fatty acid binding protein 4 (FABP4) has been shown to be important in macrophage cholesterol trafficking. The objective of the present study was to determine whether homocysteine (Hcy) accelerates AS through regulating FABP4, and then mediates cholesterol accumulation in macrophages. Hcy concentrations of 0, 50, 100, 200 and 500 µM, and 100 µM Hcy+30 µM vitamin B12 (VB12)+30 µM folic acid (FA) were respectively added to cultured THP‑1 monocyte‑derived macrophages for 24 h. The levels of FABP4, which acts as a key factor connecting cellular lipid accumulation to inflammation, were determined using reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) and western blot analyses in the macrophages. The present study used a nested touchdown methylation‑specific PCR assay to detect the DNA methylation status of the FABP4 promoter region. In addition, the FABP4 gene fragment was inserted into the cloning vector, pcDNA3.1‑EGFP, to construct the recombinant plasmid, pcDNA3.1‑EGFP/FABP4, which was identified using restriction endonuclease digestion analysis and DNA sequencing. The pcDNA3.1‑EGFP/FABP4 expression plasmid was transfected into THP‑1 monocyte‑derived macrophages, mediated by liposome reagent, following which the expression levels of FABP4 were detected using RT‑qPCR and western blot analyses. The present study also determined the intracellular accumulation of total cholesterol in the macrophages. The results indicated that Hcy decreased the levels of FABP4 promoter methylation, but increased the mRNA and protein expression levels of FABP4 in the macrophages, compared with the control group (0 µM Hcy). However, no dose

  15. Gene expression profiling of the host response to HIV-1 B, C, or A/E infection in monocyte-derived dendritic cells

    SciTech Connect

    Solis, Mayra; Wilkinson, Peter; Romieu, Raphaelle; Hernandez, Eduardo; Wainberg, Mark A.; Hiscott, John . E-mail: john.hiscott@mcgill.ca

    2006-08-15

    Dendritic cells (DC) are among the first targets of human immunodeficiency virus type-1 (HIV-1) infection and in turn play a crucial role in viral transmission to T cells and in the regulation of the immune response. The major group of HIV-1 has diversified genetically based on variation in env sequences and comprise at least 11 subtypes. Because little is known about the host response elicited against different HIV-1 clade isolates in vivo, we sought to use gene expression profiling to identify genes regulated by HIV-1 subtypes B, C, and A/E upon de novo infection of primary immature monocyte-derived DC (iMDDCs). A total of 3700 immune-related genes were subjected to a significance analysis of microarrays (SAM); 656 genes were selected as significant and were further divided into 8 functional categories. Regardless of the time of infection, 20% of the genes affected by HIV-1 were involved in signal transduction, followed by 14% of the genes identified as transcription-related genes, and 7% were classified as playing a role in cell proliferation and cell cycle. Furthermore, 7% of the genes were immune response genes. By 72 h postinfection, genes upregulated by subtype B included the inhibitor of the matrix metalloproteinase TIMP2 and the heat shock protein 40 homolog (Hsp40) DNAJB1, whereas the IFN inducible gene STAT1, the MAPK1/ERK2 kinase regulator ST5, and the chemokine CXCL3 and SHC1 genes were induced by subtypes C and A/E. These analyses distinguish a temporally regulated host response to de novo HIV-1 infection in primary dendritic cells.

  16. Comparative DNA microarray analysis of human monocyte derived dendritic cells and MUTZ-3 cells exposed to the moderate skin sensitizer cinnamaldehyde

    SciTech Connect

    Python, Francois; Goebel, Carsten; Aeby, Pierre

    2009-09-15

    The number of studies involved in the development of in vitro skin sensitization tests has increased since the adoption of the EU 7th amendment to the cosmetics directive proposing to ban animal testing for cosmetic ingredients by 2013. Several studies have recently demonstrated that sensitizers induce a relevant up-regulation of activation markers such as CD86, CD54, IL-8 or IL-1{beta} in human myeloid cell lines (e.g., U937, MUTZ-3, THP-1) or in human peripheral blood monocyte-derived dendritic cells (PBMDCs). The present study aimed at the identification of new dendritic cell activation markers in order to further improve the in vitro evaluation of the sensitizing potential of chemicals. We have compared the gene expression profiles of PBMDCs and the human cell line MUTZ-3 after a 24-h exposure to the moderate sensitizer cinnamaldehyde. A list of 80 genes modulated in both cell types was obtained and a set of candidate marker genes was selected for further analysis. Cells were exposed to selected sensitizers and non-sensitizers for 24 h and gene expression was analyzed by quantitative real-time reverse transcriptase-polymerase chain reaction. Results indicated that PIR, TRIM16 and two Nrf2-regulated genes, CES1 and NQO1, are modulated by most sensitizers. Up-regulation of these genes could also be observed in our recently published DC-activation test with U937 cells. Due to their role in DC activation, these new genes may help to further refine the in vitro approaches for the screening of the sensitizing properties of a chemical.

  17. Porcine reproductive and respiratory syndrome virus activates the transcription of interferon alpha/beta (IFN-α/β) in monocyte-derived dendritic cells (Mo-DC).

    PubMed

    Zhang, Hanmo; Guo, Xueshui; Nelson, Eric; Christopher-Hennings, Jane; Wang, Xiuqing

    2012-10-12

    Porcine reproductive and respiratory syndrome virus (PRRSV) is known to be a poor inducer of interferon alpha/beta (IFN-α/β), which may contribute to the delayed development of adaptive immunity and the resultant viral persistence. However, the exact mechanism by which PRRSV inhibits the induction of IFN-α/β during infection of its natural host cells remains less well defined. Here, we show that PRRSV efficiently activates the transcription of IFN-α/β in porcine monocyte-derived dendritic cells (Mo-DC) in a time-dependent and transient manner; and this effect is dependent on the activation of phosphatidylinositol 3-kinase (PI3K). Despite the abundant IFN-α transcripts detected in PRRSV-infected Mo-DC, little or no detectable IFN-α is found in the supernatants and cell lysates of PRRSV-infected Mo-DC, suggesting that PRRSV either blocks the translation of IFN-α or inhibits the RNA processing and transport. Furthermore, we observed that PRRSV infection significantly reduced the induction of IFN-α by Poly I:C treatment; and virus replication is essential to the effect since heat-inactivated PRRSV has no effect on IFN-α induction by Poly I:C. Overall, our data provide evidence for the possible role of PI3K in the activation of the transcription of IFN-α/β by PRRSV. We conclude that PRRSV inhibits the induction of IFN-α in Mo-DC by as yet undefined post-transcriptional mechanisms. PMID:22592217

  18. PD-L1 expression is increased in monocyte derived dendritic cells in response to porcine circovirus type 2 and porcine reproductive and respiratory syndrome virus infections.

    PubMed

    Richmond, O; Cecere, T E; Erdogan, E; Meng, X J; Piñeyro, P; Subramaniam, S; Todd, S M; LeRoith, T

    2015-11-15

    Host immune system suppression is thought to be crucial in the development of porcine circovirus associated diseases (PCVAD). Many immune suppressive mechanisms have been studied in cases of PCVAD, however, the role of programmed death ligand-1 (PD-L1) during porcine circovirus type 2 (PCV2) infection and PCVAD development has yet to be determined. PD-L1 has become an important research target because of its ability to interfere with effective T-cell activity and proliferation during the course of an immune response. In this study, porcine monocyte derived dendritic cells (MoDC) were infected with different combinations of PCV2 and porcine reproductive and respiratory syndrome virus (PRRSV) and evaluated for expression levels of PD-L1, as well as the expression levels of swine major histocompatibility complexes 1 and 2 (SLA-1 and SLA-2) as a measure of MoDC stimulatory capacity. PD-L1 expression levels were also tested in MoDCs after treatment with interferon alpha (IFN-α) and beta (IFN-β). The results showed that the expression levels of PD-L1 were increased in PCV2-infected MoDCs, as well as in PCV2 and PRRSV co-infected MoDCs. The MoDCs infected with PRRSV only also showed a strain-dependent increase in PD-L1 expression. Both IFN-α and IFN-β treatment also increased the expression levels of PD-L1 in MoDCs. SLA-1 and 2 expression levels were increased by PCV2 infection, and altered in the PRRSV, and PCV2+PRRSV co-infected MoDCs in a strain-dependent manner. These results indicate a potential immuno-suppressive role for dendritic cells during PCV2 infection and the development of PCVAD and will be helpful in more fully elucidating the underlying mechanisms leading to clinical PCVAD. PMID:26553563

  19. Dendritic Cell (DC) Vaccine in Mouse Lung Cancer Minimal Residual Model; Comparison of Monocyte-derived DC vs. Hematopoietic Stem Cell Derived-DC.

    PubMed

    Baek, Soyoung; Lee, Seog Jae; Kim, Myoung Joo; Lee, Hyunah

    2012-12-01

    The anti-tumor effect of monocyte-derived DC (MoDC) vaccine was studied in lung cancer model with feasible but weak Ag-specific immune response and incomplete blocking of tumor growth. To overcome this limitation, the hematopoietic stem cell-derived DC (SDC) was cultured and the anti-tumor effect of MoDC & SDC was compared in mouse lung cancer minimal residual model (MRD). Therapeutic DCs were cultured from either CD34(+) hematopoietic stem cells with GM-CSF, SCF and IL-4 for 14 days (SDC) or monocytes with GM-CSF and IL-4 for 7 days (MoDC). DCs were injected twice by one week interval into the peritoneum of mice that are inoculated with Lewis Lung Carcinoma cells (LLC) one day before the DC injection. Anti-tumor responses and the immune modulation were observed 3 weeks after the final DC injection. CD11c expression, IL-12 and TGF-β secretion were higher in SDC but CCR7 expression, IFN-γ and IL-10 secretion were higher in MoDC. The proportion of CD11c(+)CD8a(+) cells was similar in both DC cultures. Although both DC reduced the tumor burden, histological anti-tumor effect and the frequencies of IFN-γ secreting CD8(+) T cells were higher in SDC treated group than in MoDC. Conclusively, although both MoDC and SDC can induce the anti-tumor immunity, SDC may be better module as anti-tumor vaccine than MoDC in mouse lung cancer. PMID:23396889

  20. Binding immunoglobulin protein-treated peripheral blood monocyte-derived dendritic cells are refractory to maturation and induce regulatory T-cell development.

    PubMed

    Corrigall, Valerie M; Vittecoq, Olivier; Panayi, Gabriel S

    2009-10-01

    Binding immunoglobulin protein (BiP) has been shown previously to have immunomodulatory functions. Herein we investigated whether BiP could affect the differentiation of monocytes into dendritic cells (DCs) and thence the development of regulatory T cells. Peripheral blood monocyte-derived DCs were matured with lipopolysaccharide in the presence or absence of BiP. DC development and T-cell changes were monitored by flow cytometry and regulatory T-cell function was measured by uptake of tritiated thymidine. More BiP-treated DCs (DC((BiP))s) expressed amounts of intracellular indoleamine 2,3-dioxygenase (IDO) and cell surface leucocyte immunoglobulin-like receptor subfamily B member 1 (LILRB1), retained CD14 expression but down-regulated expression of human leucocyte antigen (HLA)-DR and CD86, and produced copious amounts of interleukin (IL)-10, when compared with control DCs. T cells co-cultured with DC((BiP))s developed regulatory function with increased surface expression of CD4(+) CD25(hi) CD27(hi) but with no concomitant increase in forkhead box P3 (Foxp3). These T cells also showed significantly higher levels of intracellular cytotoxic T-lymphocyte antigen (CTLA)-4. The latter could be inhibited by the presence of the IDO inhibitor 1 methyl tryptophan. The addition of neutralizing anti-IL-10 antibody or the specific mitogen-activated protein kinase (MAPK) p38 inhibitor SB203580 reversed the inhibition of DC differentiation by BiP. In conclusion, BiP is an immunomodulator able to arrest inflammation through induction of tolerogenic DCs and subsequent generation of T regulatory cells. PMID:19740378

  1. Validation of efficient high-throughput plasmid and siRNA transfection of human monocyte-derived dendritic cells without cell maturation.

    PubMed

    Bowles, Robert; Patil, Sonali; Pincas, Hanna; Sealfon, Stuart C

    2010-12-15

    Transfection of primary immune cells is difficult to achieve at high efficiency and without cell activation and maturation. Dendritic cells (DCs) represent a key link between the innate and adaptive immune systems. Delineating the signaling pathways involved in the activation of human primary DCs and reverse engineering cellular inflammatory pathways have been challenging tasks. We optimized and validated an effective high-throughput transfection protocol, allowing us to transiently express DNA in naïve primary DCs, as well as investigate the effect of gene silencing by RNA interference. Using a high-throughput nucleofection system, monocyte-derived DCs were nucleoporated with a plasmid expressing green fluorescent protein (GFP), and transfection efficiency was determined by flow cytometry, based on GFP expression. To evaluate the effect of nucleoporation on DC maturation, the expression of cell surface markers CD86 and MHCII in GFP-positive cells was analyzed by flow cytometry. We established optimal assay conditions with a cell viability reaching 70%, a transfection efficiency of over 50%, and unchanged CD86 and MHCII expression. We examined the impact of small interfering RNA (siRNA)-mediated knockdown of RIG-I, a key viral recognition receptor, on the induction of the interferon (IFN) response in DCs infected with Newcastle disease virus. RIG-I protein was undetectable by Western blot in siRNA-treated cells. RIG-I knockdown caused a 75% reduction in the induction of IFNβ mRNA compared with the negative control siRNA. This protocol should be a valuable tool for probing the immune response pathways activated in human DCs. PMID:20875421

  2. Evaluation of the sensitizing potential of antibiotics in vitro using the human cell lines THP-1 and MUTZ-LC and primary monocyte-derived dendritic cells.

    PubMed

    Sebastian, Katrin; Ott, Hagen; Zwadlo-Klarwasser, Gabriele; Skazik-Voogt, Claudia; Marquardt, Yvonne; Czaja, Katharina; Merk, Hans F; Baron, Jens Malte

    2012-08-01

    Since the 7th amendment to the EU cosmetics directive foresees a complete ban on animal testing, alternative in vitro methods have been established to evaluate the sensitizing potential of small molecular weight compounds. To find out whether these novel in vitro assays are also capable to predict the sensitizing potential of small molecular weight drugs, model compounds such as beta-lactams and sulfonamides - which are the most frequent cause of adverse drug reactions - were co-incubated with THP-1, MUTZ-LC, or primary monocyte-derived dendritic cells for 48 h and subsequent expression of selected marker genes (IL-8, IL-1β, CES1, NQO1, GCLM, PIR and TRIM16) was studied by real time PCR. Benzylpenicillin and phenoxymethylpenicillin were recognized as sensitizing compounds because they are capable to induce the mRNA expression of these genes in moDCs and, except for IL-8, in THP-1 cells but not in MUTZ-LC. Ampicillin stimulated the expression of some marker genes in moDCs and THP-1 cells. SMX did not affect the expression of these genes in THP-1, however, in moDCs, at least PIR was enhanced and there was an increase of the release of IL-8. These data reveal that novel in vitro DC based assays might play a role in the evaluation of the allergenic potential of novel drug compounds, but these systems seem to lack the ability to detect the sensitizing potential of prohaptens that require metabolic activation prior to sensitization and moDCs seem to be superior with regard to the sensitivity compared with THP-1 and MUTZ-3 cell lines. PMID:22609641

  3. Effects of T cell immunoglobulin and mucin domain-containing molecule-3 signaling molecule on human monocyte-derived dendritic cells with hepatitis B virus surface antigen stimulation in vitro.

    PubMed

    Yu, Zhenjun; Jiang, Ting; Zhu, Min; Pan, Kechuan; Yan, Fei; Zhu, Jiansheng

    2016-03-01

    The aim of the present study was to investigate the in vitro effects of hepatitis B virus surface antigen (HBsAg) on the immune function of human monocyte-derived dendritic cells (MD‑DCs), and the moderating role of T cell immunoglobulin and mucin domain‑containing molecule‑3 (Tim‑3) signaling molecule. The monocytes, obtained from healthy adult peripheral blood, were incubated with recombinant human granulocyte‑macrophage colony‑stimulating factor and interleukin (IL)‑4 to induce DCs. DC‑associated cell markers were detected using flow cytometry. MD‑DCs were treated with HBsAg (5 µg/ml) in vitro for 48 h and subsequently, cell markers, lymphocyte stimulatory capacity, signaling protein and downstream cytokines were assessed. In addition, a Tim‑3 monoclonal antibody was used to inhibit the Tim‑3 signaling pathway, and subsequently the immune responses of MD‑DCs to HBsAg stimulation were determined using the aforementioned method. The cell phenotype expressions of MD‑DCs were all significantly increased with cluster of differentiation (CD)11c at 70.09±0.57%, human leukocyte antigen‑DR at 79.83±2.12%, CD80 at 48.33±7.34% and CD86 at 44.21±5.35%. The treatment of MD‑DCs with HBsAg resulted in a CD80 and CD86 enhanced expression, enhanced lymphocyte stimulatory capacity, upregulated expression of Tim‑3 and nuclear factor‑κB (NF‑κB), as well as enhanced cytokine secretion of IL‑6, IL‑10 and interferon (IFN)‑γ. However, a reduced immune response of MD‑DCs in response to HBsAg stimulation was observed when the Tim‑3 signaling pathway was inhibited prior to stimulation. The expression of NF‑κB was decreased and the cytokine secretion level of IL‑6, IL‑10 and IFN‑γ were downregulated. The treatment with HBsAg in vitro resulted in an enhanced immune response of MD‑DCs, which may be positively regulated by the Tim-3 signaling molecule. PMID:26820685

  4. Investigating the Role of Surface Materials and Three Dimensional Architecture on In Vitro Differentiation of Porcine Monocyte-Derived Dendritic Cells

    PubMed Central

    Hartmann, Sofie Bruun; Mohanty, Soumyaranjan; Skovgaard, Kerstin; Brogaard, Louise; Flagstad, Frederikke Bjergvang; Emnéus, Jenny; Wolff, Anders; Summerfield, Artur; Jungersen, Gregers

    2016-01-01

    In vitro generation of dendritic-like cells through differentiation of peripheral blood monocytes is typically done using two-dimensional polystyrene culture plates. In the process of optimising cell culture techniques, engineers have developed fluidic micro-devises usually manufactured in materials other than polystyrene and applying three-dimensional structures more similar to the in vivo environment. Polydimethylsiloxane (PDMS) is an often used polymer for lab-on-a-chip devices but not much is known about the effect of changing the culture surface material from polystyrene to PDMS. In the present study the differentiation of porcine monocytes to monocyte-derived dendritic cells (moDCs) was investigated using CD172apos pig blood monocytes stimulated with GM-CSF and IL-4. Monocytes were cultured on surfaces made of two- and three-dimensional polystyrene as well as two- and three-dimensional PDMS and carbonised three-dimensional PDMS. Cells cultured conventionally (on two-dimensional polystyrene) differentiated into moDCs as expected. Interestingly, gene expression of a wide range of cytokines, chemokines, and pattern recognition receptors was influenced by culture surface material and architecture. Distinct clustering of cells, based on similar expression patterns of 46 genes of interest, was seen for cells isolated from two- and three-dimensional polystyrene as well as two- and three-dimensional PDMS. Changing the material from polystyrene to PDMS resulted in cells with expression patterns usually associated with macrophage expression (upregulation of CD163 and downregulation of CD1a, FLT3, LAMP3 and BATF3). However, this was purely based on gene expression level, and no functional assays were included in this study which would be necessary in order to classify the cells as being macrophages. When changing to three-dimensional culture the cells became increasingly activated in terms of IL6, IL8, IL10 and CCR5 gene expression. Further stimulation with LPS resulted

  5. Proteomic analyses of monocyte-derived macrophages infected with human immunodeficiency virus type 1 primary isolates from Hispanic women with and without cognitive impairment

    PubMed Central

    Toro-Nieves, DM; Rodriguez, Y; Plaud, M; Ciborowski, P; Duan, F; Laspiur, J Pérez; Wojna, V; Meléndez, LM

    2009-01-01

    The signature for human immunodeficiency virus type 1 (HIV-1) neurovirulence remains a subject of intense debate. Macrophage viral tropism is one prerequisite but others, including virus-induced alterations in innate and adaptive immunity, remain under investigation. HIV-1–infected mononuclear phagocytes (MPs; perivascular macrophages and microglia) secrete toxins that affect neurons. The authors hypothesize that neurovirulent HIV-1 variants affect the MP proteome by inducing a signature of neurotoxic proteins and thus affect cognitive function. To test this hypothesis, HIV-1 isolates obtained from peripheral blood of women with normal cognition (NC) were compared to isolates obtained from women with cognitive impairment (CI) and to the laboratory adapted SF162, a spinal fluid R5 isolate from a patient with HIV-1–associated dementia. HIV-1 isolates were used to infect monocyte-derived macrophages (MDMs) and infection monitored by secreted HIV-1 p24 by enzyme-linked immunosorbent assay (ELISA). Cell lysates of uninfected and HIV-1–infected MDMs at 14 days post infection were fractionated by cationic exchange chromatography and analyzed by surface enhanced laser desorption ionization time of flight (SELDI-TOF) using generalized estimating equations statistics. Proteins were separated by one-dimensional sodium dodecyl sulfate–polyacrylamide gel electrophoresis (1D SDS-PAGE) and identified by tandem mass spectrometry. Levels of viral replication were similar amongst the HIV-1 isolates, although higher levels were obtained from one viral strain obtained from a patient with CI. Significant differences were found in protein profiles between virus-infected MDMs with NC, CI, and SF162 isolates (adjusted P value after multiple testing corrections, or q value < .10). The authors identified 6 unique proteins in NC, 7 in SF162, and 20 in CI. Three proteins were common to SF162 and CI strains. The MDM proteins linked to infection with CI strains were related to apoptosis

  6. Binding of the 68-kilodalton protein of Mycobacterium avium to alpha(v)beta3 on human monocyte-derived macrophages enhances complement receptor type 3 expression.

    PubMed Central

    Hayashi, T; Rao, S P; Catanzaro, A

    1997-01-01

    Attachment to and uptake by host cells are important early events in the pathogenesis of intracellular organisms such as Mycobacterium avium. Monocyte-derived macrophages (MDM) are known to express multiple surface receptors that play a role in binding to and uptake of M. avium. These include complement receptor type 3 (CR3), fibronectin receptor, mannose receptor, and transferrin receptor. In addition to these, we have previously reported that the integrin receptor alpha(v)beta3 also plays a role in binding to M. avium in a nonopsonic environment. Further, we have shown that a 68-kDa surface protein of M. avium binds to human monocytes and plays a role in attachment of M. avium to MDM. The present study provides direct evidence that this protein mediates attachment of M. avium to MDM by binding to alpha(v)beta3. Using the technique of cell surface enzyme-linked immunosorbent assay, we have shown that the M. avium 68-kDa protein inhibits the binding of monoclonal antibodies (MAb) against alpha(v)beta3 to MDM compared to control proteins such as ovalbumin and laminin (P < 0.05). Dual-labeling studies were performed to demonstrate that after phagocytosis, alpha(v)beta3 is present along with M. avium in phagosomes of M. avium-infected MDM. In addition, we have demonstrated that this interaction between alpha(v)beta3 and the M. avium 68-kDa protein resulted in enhancement of CR3 expression, which is known to play a role in complement-mediated uptake of M. avium. Attachment of MDM to wells coated with the M. avium 68-kDa protein resulted in a twofold increase in CR3 expression compared to attachment of MDM to wells coated with ovalbumin. This enhancement was completely inhibited by pretreatment of MDM with MAb against alpha(v)beta3. In summary, M. avium binds to MDM via alpha(v)beta3 with the help of the M. avium 68-kDa protein, and this ligation enhanced the expression of CR3 on MDM. Since CR3 has been known to play a role in M. avium uptake, enhanced expression of

  7. Bromelain treatment leads to maturation of monocyte-derived dendritic cells but cannot replace PGE2 in a cocktail of IL-1β, IL-6, TNF-α and PGE2.

    PubMed

    Karlsen, M; Hovden, A-O; Vogelsang, P; Tysnes, B B; Appel, S

    2011-08-01

    Immunotherapy using dendritic cells (DC) has shown promising results. However, the use of an appropriate DC population is critical for the outcome of this treatment, and the search for an optimal DC subset is still ongoing. The DC used in immunotherapy today are usually matured with a cytokine cocktail consisting of TNF-α, IL-1β, IL-6 and PGE(2). These cells have deficits in their cytokine production, particularly IL-12p70, mainly because of the presence of PGE(2). Bromelain is a pineapple stem extract containing a mixture of proteases that has been used clinically in adjuvant cancer treatment. In this study, we analysed the effect of bromelain on human monocyte-derived DC. We added bromelain to the cytokine cocktail and modified cytokine cocktails with either no PGE(2) or reduced amounts of PGE(2), respectively. Combining bromelain with the cytokine cocktails containing PGE(2) resulted in an increased surface expression of CD83, CD80 and CD86. The chemokine receptor CCR7 was also considerably upregulated in these DC populations compared with DC treated with the cytokine cocktail alone. Removal or reduction of PGE(2) from the cytokine cocktail did not increase the IL-12p70 secretion from stimulated DC, and addition of bromelain to the different cytokine cocktails resulted in only a minor increase in IL-12p70 production. Moreover, combining bromelain with the cytokine cocktails did not improve the T cell stimulatory capacity of the generated DC populations. In conclusion, bromelain treatment of monocyte-derived DC does not improve the functional quality compared with the standard cytokine cocktail. PMID:21449940

  8. Physiological function and inflamed-brain migration of mouse monocyte-derived macrophages following cellular uptake of superparamagnetic iron oxide nanoparticles-Implication of macrophage-based drug delivery into the central nervous system.

    PubMed

    Tong, Hsin-I; Kang, Wen; Shi, Yingli; Zhou, Guangzhou; Lu, Yuanan

    2016-05-30

    This study was designed to use superparamagnetic iron oxide nanoparticles (SPIONs) as evaluating tools to study monocyte-derived macrophages (MDM)-mediated delivery of small molecular agents into the diseased brains. MDM were tested with different-configured SPIONs at selected concentrations for their impacts on carrier cells' physiological and migratory properties, which were found to depend largely on particle size, coating, and treatment concentrations. SHP30, a SPION of 30-nm core size with oleic acids plus amphiphilic polymer coating, was identified to have high cellular uptake efficiency and cause little cytotoxic effects on MDM. At lower incubation dose (25μg/mL), few alteration was observed in carrier cells' physiological and in vivo migratory functions, as tested in a lipopolysaccharide-induced acute neuroinflammation mouse model. Nevertheless, significant increase in monocyte-to-macrophage differentiation, and decrease in in vivo carrier MDM inflamed-brain homing ability were found in groups treated with a higher dose of SHP30at 100μg/mL. Overall, our results have identified MDM treatment at 25μg/mL SHP30 resulted in little functional changes, provided valuable parameters for using SPIONs as evaluating tools to study MDM-mediated therapeutics carriage and delivery, and supported the concepts of using monocytes-macrophages as cellular vehicles to transport small molecular agents to the brain. PMID:27001531

  9. Activation and cytokine profile of monocyte derived dendritic cells in leprosy: in vitro stimulation by sonicated Mycobacterium leprae induces decreased level of IL-12p70 in lepromatous leprosy.

    PubMed

    Braga, André Flores; Moretto, Daniela Ferraz; Gigliotti, Patrícia; Peruchi, Mariela; Vilani-Moreno, Fátima Regina; Campanelli, Ana Paula; Latini, Ana Carla Pereira; Iyer, Anand; Das, Pranab Kumar; Souza, Vânia Nieto Brito de

    2015-08-01

    Dendritic cells (DCs) play a pivotal role in the connection of innate and adaptive immunity of hosts to mycobacterial infection. Studies on the interaction of monocyte-derived DCs (MO-DCs) using Mycobacterium leprae in leprosy patients are rare. The present study demonstrated that the differentiation of MOs to DCs was similar in all forms of leprosy compared to normal healthy individuals. In vitro stimulation of immature MO-DCs with sonicated M. leprae induced variable degrees of DC maturation as determined by the increased expression of HLA-DR, CD40, CD80 and CD86, but not CD83, in all studied groups. The production of different cytokines by the MO-DCs appeared similar in all of the studied groups under similar conditions. However, the production of interleukin (IL)-12p70 by MO-DCs from lepromatous (LL) leprosy patients after in vitro stimulation with M. leprae was lower than tuberculoid leprosy patients and healthy individuals, even after CD40 ligation with CD40 ligand-transfected cells. The present cumulative findings suggest that the MO-DCs of LL patients are generally a weak producer of IL-12p70 despite the moderate activating properties ofM. leprae. These results may explain the poor M. leprae-specific cell-mediated immunity in the LL type of leprosy. PMID:26222022

  10. Differential regulatory activities of viral protein X for anti-viral efficacy of nucleos(t)ide reverse transcriptase inhibitors in monocyte-derived macrophages and activated CD4(+) T cells.

    PubMed

    Hollenbaugh, Joseph A; Schader, Susan M; Schinazi, Raymond F; Kim, Baek

    2015-11-01

    Vpx encoded by HIV-2 and SIVsm enhances retroviral reverse transcription in macrophages in vitro by mediating the degradation of the host SAMHD1 protein that hydrolyzes dNTPs and by elevating cellular dNTP levels. Here we employed RT-SHIV constructs (SIV encoding HIV-1 RT) to investigate the contribution of Vpx to the potency of NRTIs, which compete against dNTPs, in monocyte-derived macrophages (MDMs) and activated CD4(+) T cells. Relative to HIV-1, both SIV and RT-SHIV exhibited reduced sensitivities to AZT, 3TC and TDF in MDMs but not in activated CD4(+) T cells. However, when SIV and RT-SHIV constructs not coding for Vpx were utilized, we observed greater sensitivities to all NRTIs tested using activated CD4(+) T cells relative to the Vpx-coding counterparts. This latter phenomenon was observed for AZT only when using MDMs. Our data suggest that Vpx in RT-SHIVs may underestimate the antiviral efficacy of NRTIs in a cell type dependent manner. PMID:26319213

  11. Activation and cytokine profile of monocyte derived dendritic cells in leprosy: in vitro stimulation by sonicated Mycobacterium leprae induces decreased level of IL-12p70 in lepromatous leprosy

    PubMed Central

    Braga, André Flores; Moretto, Daniela Ferraz; Gigliotti, Patrícia; Peruchi, Mariela; Vilani-Moreno, Fátima Regina; Campanelli, Ana Paula; Latini, Ana Carla Pereira; Iyer, Anand; Das, Pranab Kumar; de Souza, Vânia Nieto Brito

    2015-01-01

    Dendritic cells (DCs) play a pivotal role in the connection of innate and adaptive immunity of hosts to mycobacterial infection. Studies on the interaction of monocyte-derived DCs (MO-DCs) using Mycobacterium leprae in leprosy patients are rare. The present study demonstrated that the differentiation of MOs to DCs was similar in all forms of leprosy compared to normal healthy individuals. In vitro stimulation of immature MO-DCs with sonicated M. leprae induced variable degrees of DC maturation as determined by the increased expression of HLA-DR, CD40, CD80 and CD86, but not CD83, in all studied groups. The production of different cytokines by the MO-DCs appeared similar in all of the studied groups under similar conditions. However, the production of interleukin (IL)-12p70 by MO-DCs from lepromatous (LL) leprosy patients after in vitro stimulation with M. leprae was lower than tuberculoid leprosy patients and healthy individuals, even after CD40 ligation with CD40 ligand-transfected cells. The present cumulative findings suggest that the MO-DCs of LL patients are generally a weak producer of IL-12p70 despite the moderate activating properties ofM. leprae. These results may explain the poor M. leprae-specific cell-mediated immunity in the LL type of leprosy. PMID:26222022

  12. Plasma visfatin levels and mRNA expression of visfatin in peripheral blood mononuclear cells and peripheral blood monocyte-derived macrophages from normal weight females with polycystic ovary syndrome

    PubMed Central

    ZHANG, JING; ZHOU, LINGLING; TANG, LIULIN; XU, LIANGZHI

    2014-01-01

    Polycystic ovary syndrome (PCOS) is a common reproductive endocrinology disease, however, an explicit etiology is not known. Insulin resistance (IR) appears to be central to the pathogenesis of PCOS and inflammation may be significant in the pathogenesis of IR in PCOS. The aims of the present study were to investigate the plasma visfatin level and the gene expression of visfatin in peripheral blood mononuclear cells (PBMCs) and peripheral blood monocyte-derived macrophages (PBMMs) from PCOS patients, in addition to investigating the association between PCOS and IR. A total of 21 PCOS patients and 21 control subjects were enrolled in the study; the homeostasis model assessment of insulin resistance (HOMA-IR) was considered to be a stratified method for establishing the subgroups. Fasting blood samples were collected and the levels of sex hormones, insulin, glucose, blood lipids and visfatin were measured. In addition, visfatin gene expression levels in PBMCs and PBMMs were assessed using quantitative polymerase chain reaction. The plasma visfatin and gene expression levels of visfatin in PBMCs and PBMMs were not observed to increase in the normal weight PCOS and normal weight IR patients. Furthermore, plasma visfatin levels did not correlate with the normal weight PCOS patients or the normal weight IR patients per se. Further investigation into the role of visfatin in the pathogenesis of PCOS or IR should examine macrophages in the tissues, rather than macrophages in the peripheral blood. PMID:24940414

  13. Cord blood monocyte-derived inflammatory cytokines suppress IL-2 and induce nonclassic "T(H)2-type" immunity associated with development of food allergy.

    PubMed

    Zhang, Yuxia; Collier, Fiona; Naselli, Gaetano; Saffery, Richard; Tang, Mimi L K; Allen, Katrina J; Ponsonby, Anne-Louise; Harrison, Leonard C; Vuillermin, Peter

    2016-01-13

    Food allergy is a major health burden in early childhood. Infants who develop food allergy display a proinflammatory immune profile in cord blood, but how this is related to interleukin-4 (IL-4)/T helper 2 (T(H)2)-type immunity characteristic of allergy is unknown. In a general population-derived birth cohort, we found that in infants who developed food allergy, cord blood displayed a higher monocyte to CD4(+) T cell ratio and a lower proportion of natural regulatory T cell (nT(reg)) in relation to duration of labor. CD14(+) monocytes of food-allergic infants secreted higher amounts of inflammatory cytokines (IL-1β, IL-6, and tumor necrosis factor-α) in response to lipopolysaccharide. In the presence of the mucosal cytokine transforming growth factor-β, these inflammatory cytokines suppressed IL-2 expression by CD4(+) T cells. In the absence of IL-2, inflammatory cytokines decreased the number of activated nT(reg) and diverted the differentiation of both nT(reg) and naïve CD4(+) T cells toward an IL-4-expressing nonclassical TH2 phenotype. These findings provide a mechanistic explanation for susceptibility to food allergy in infants and suggest anti-inflammatory approaches to its prevention. PMID:26764159

  14. Monocyte derived IL 10 and PGE2 are associated with the absence of Th 1 cells and in vitro T cell suppression in lepromatous leprosy.

    PubMed

    Misra, N; Selvakumar, M; Singh, S; Bharadwaj, M; Ramesh, V; Misra, R S; Nath, I

    1995-12-01

    Our previous studies had shown that the clinicopathological spectrum in leprosy was associated with discrete T cell subsets in circulation, with tuberculoid patients having antigen-induced Th 1, whereas lepromatous leprosy patients with antigen-specific T cell anergy possessed Th 2 cells. The present study shows that infected monocytes from lepromatous but not tuberculoid leprosy patients released soluble factors (MoF(s)) containing IL-10 and PGE2 which inhibited M. leprae induced in vitro lymphoproliferation of previously sensitised healthy or tuberculoid leprosy subjects. A strong negative correlation was observed between adherent cell derived IL-10 and IL-2 at the level of both the product and cytokine mRNA. Moreover, anti-IL-10 antibodies and indomethacin partially reversed the suppressor effects of MoF(s). Taken together these studies indicate that infected monocytes contribute to the development of T cell anergy by releasing factors that affect regulatory cytokines and T cell subset differentiation in lepromatous leprosy. PMID:8719110

  15. Infection of human monocyte-derived dendritic cells by ANDES Hantavirus enhances pro-inflammatory state, the secretion of active MMP-9 and indirectly enhances endothelial permeability

    PubMed Central

    2011-01-01

    Background Andes virus (ANDV), a rodent-borne Hantavirus, is the major etiological agent of Hantavirus cardiopulmonary syndrome (HCPS) in South America, which is mainly characterized by a vascular leakage with high rate of fatal outcomes for infected patients. Currently, neither specific therapy nor vaccines are available against this pathogen. ANDV infects both dendritic and epithelial cells, but in despite that the severity of the disease directly correlates with the viral RNA load, considerable evidence suggests that immune mechanisms rather than direct viral cytopathology are responsible for plasma leakage in HCPS. Here, we assessed the possible effect of soluble factors, induced in viral-activated DCs, on endothelial permeability. Activated immune cells, including DC, secrete gelatinolytic matrix metalloproteases (gMMP-2 and -9) that modulate the vascular permeability for their trafficking. Methods A clinical ANDES isolate was used to infect DC derived from primary PBMC. Maturation and pro-inflammatory phenotypes of ANDES-infected DC were assessed by studying the expression of receptors, cytokines and active gMMP-9, as well as some of their functional status. The ANDES-infected DC supernatants were assessed for their capacity to enhance a monolayer endothelial permeability using primary human vascular endothelial cells (HUVEC). Results Here, we show that in vitro primary DCs infected by a clinical isolate of ANDV shed virus RNA and proteins, suggesting a competent viral replication in these cells. Moreover, this infection induces an enhanced expression of soluble pro-inflammatory factors, including TNF-α and the active gMMP-9, as well as a decreased expression of anti-inflammatory cytokines, such as IL-10 and TGF-β. These viral activated cells are less sensitive to apoptosis. Moreover, supernatants from ANDV-infected DCs were able to indirectly enhance the permeability of a monolayer of primary HUVEC. Conclusions Primary human DCs, that are primarily

  16. In vitro impact of bisphenols BPA, BPF, BPAF and 17β-estradiol (E2) on human monocyte-derived dendritic cell generation, maturation and function.

    PubMed

    Švajger, Urban; Dolenc, Marija Sollner; Jeras, Matjaž

    2016-05-01

    Bisphenols (BPs) are widely spread pollutants that act as estrogen-like endocrine disruptors and are potentially affecting human health on a long run. We explored the effects of BPA, BPF and BPAF, on in vitro differentiation and maturation of MDDCs. Monocytes were treated with 17β-estradiol (E2) and each BP at the beginning of their differentiation into iMDDCs. We found that 10 and 50 μM of BPA and BPF, 10 and 30μM of BPAF and 10 and 50 nM of E2 did not affect cell viability. However, 50 μM of BPA and BPF, as well as 10 and 30 μM of BPAF, significantly decreased the endocytotic capacity of iMDDCs. Both, BPA (50 μM) and BPAF (30 μM) decreased the expression of CD1a and increased the amount of DC-SIGN molecules on iMDDCs. The E2 pre-treatment moderately decreased expression of CD80, CD86 and CD83 co-stimulatory molecules while increasing the numbers of HLA-DR on mMDDCs. Only BPAF significantly influenced the expression of CD80 and CD86 (both decreased), as well as CD83 and HLA-DR molecules (both increased) on mMDDCs. In addition, BPAF modulated DC maturation signaling pathways by lowering the phosphorylation of p65 NF-κB (nuclear factor-kappaB) and ERK (extracellular signal regulated kinase) 1/2 proteins. Consequently, the in vitro proliferation of allogeneic T cells, stimulated with differently pre-treated iMDDCs and mMDDCs, was significantly reduced only in case of BPAF. PMID:26945833

  17. PAF-degrading acetylhydrolase is preferentially associated with dense LDL and VHDL-1 in human plasma. Catalytic characteristics and relation to the monocyte-derived enzyme.

    PubMed

    Tselepis, A D; Dentan, C; Karabina, S A; Chapman, M J; Ninio, E

    1995-10-01

    In human plasma, platelet activating factor (PAF)-degrading acetylhydrolase (acetylhydrolase) is principally transported in association with LDLs and HDLs; this enzyme hydrolyzes PAF and short-chain forms of oxidized phosphatidylcholine, transforming them into lyso-PAF and lysophosphatidylcholine, respectively. We have examined the distribution, catalytic characteristics, and transfer of acetylhydrolase activity among plasma lipoprotein subspecies separated by isopycnic density gradient ultracentrifugation; the possibility that the plasma enzyme may be partially derived from adherent monocytes has also been evaluated. In normolipidemic subjects with Lp(a) levels < 0.1 mg/mL, acetylhydrolase was associated preferentially with small, dense LDL particles (LDL-5; d = 1.050 to 1.063 g/mL) and with the very-high-density lipoprotein-1 subfraction (VHDL-1; d = 1.156 to 1.179 g/mL), representing 23.9 +/- 1.7% and 20.6 +/- 3.2%, respectively, of total plasma activity. The apparent Km values for PAF of the enzyme associated with such lipoproteins were 89.7 +/- 23.4 and 34.8 +/- 4.5 mumol/L for LDL-5 and VHDL-1, respectively: indeed, the Km value for LDL-5 was some 10-fold higher than that of the light LDL-1, LDL-2, and LDL-3 subspecies, whereas the Km of VHDL-1 was some twofold greater than those of the HDL-2 and HDL-3 subspecies. Furthermore, when expressed on the basis of unit plasma volume, the Vmax of the acetylhydrolase associated with LDL-5 was some 150-fold greater than that in LDL-1 (d = 1.019 to 1.023 g/mL). No significant differences in the pH dependence of enzyme activity or in sensitivity to protease inactivation, sulfydryl reagents, the serine protease inhibitor Pefabloc, or the PAF antagonist CV 3988 could be detected between apo B-containing and apo A-I-containing lipoprotein particle subspecies. Incubation of LDL-1 (Km = 8.4 +/- 2.6 mumol/L) and LDL-2 (d = 1.023 to 1.029 g/mL; Km = 8.4 +/- 3.3 mumol/L) subspecies with LDL-5, in which acetylhydrolase had been

  18. Addition of CpG ODN and Poly (I:C) to a standard maturation cocktail generates monocyte-derived dendritic cells and induces a potent Th1 polarization with migratory capacity

    PubMed Central

    Zhu, Mei; Xu, Wei; Su, Hong; Huang, Qiong; Wang, Baolong

    2015-01-01

    Monocyte-derived dendritic cells (DCs) are used as immunoadjuvant cells in cancer vaccines and have made great progress. However, an optimal DCs subset is vital for this treatment effect, the current ′gold standard′ cytokine cocktail DCs have a shortcoming in their cytokines secretion, especially IL-12p70, mainly because of the existence of PGE2. Therefore, it is necessary to find an appropriate DCs-based immunotherapeutic protocol. In this study, we compared a novel ′improved′ maturation cytokine cocktail with the current ′gold standard′ maturation cytokine cocktail used for generating standard DCs. The ′improved′ maturation cytokine cocktail DCs showed a higher levels surface markers expression (CD80, CD83, CD86 and HLA-DR), the chemokine receptors CXCR4 and CCR7 and chemokine CCL19, CCL21 and CXCL21, whereas CCR5 expression was reduced. Most importantly, in contrast to ′gold standard′ DCs, which secrete little IL-12p70 and as a result induce mainly Th2 immunity, ′improved′ cytokine cocktail DCs secreted higher levels IL-12p70 and also secreted similar concentration IL-10. To removal of PGE2 from the ′improved′ DCs did increase the IL-12p70 production. In conclusion, we here present the ′improved′ DCs, as an optimal maturation cocktail protocol, can induce high migratory potential, generate immunostimulatory DCs, produce higher levels IL-12p70 with superior capacity to induce Th1 immunity, when compared with the ′gold standard′ DCs. PMID:26039883

  19. Psychedelic N,N-Dimethyltryptamine and 5-Methoxy-N,N-Dimethyltryptamine Modulate Innate and Adaptive Inflammatory Responses through the Sigma-1 Receptor of Human Monocyte-Derived Dendritic Cells

    PubMed Central

    Szabo, Attila; Kovacs, Attila

    2014-01-01

    The orphan receptor sigma-1 (sigmar-1) is a transmembrane chaperone protein expressed in both the central nervous system and in immune cells. It has been shown to regulate neuronal differentiation and cell survival, and mediates anti-inflammatory responses and immunosuppression in murine in vivo models. Since the details of these findings have not been elucidated so far, we studied the effects of the endogenous sigmar-1 ligands N,N-dimethyltryptamine (NN-DMT), its derivative 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and the synthetic high affinity sigmar-1 agonist PRE-084 hydrochloride on human primary monocyte-derived dendritic cell (moDCs) activation provoked by LPS, polyI:C or pathogen-derived stimuli to induce inflammatory responses. Co-treatment of moDC with these activators and sigma-1 receptor ligands inhibited the production of pro-inflammatory cytokines IL-1β, IL-6, TNFα and the chemokine IL-8, while increased the secretion of the anti-inflammatory cytokine IL-10. The T-cell activating capacity of moDCs was also inhibited, and dimethyltryptamines used in combination with E. coli or influenza virus as stimulators decreased the differentiation of moDC-induced Th1 and Th17 inflammatory effector T-cells in a sigmar-1 specific manner as confirmed by gene silencing. Here we demonstrate for the first time the immunomodulatory potential of NN-DMT and 5-MeO-DMT on human moDC functions via sigmar-1 that could be harnessed for the pharmacological treatment of autoimmune diseases and chronic inflammatory conditions of the CNS or peripheral tissues. Our findings also point out a new biological role for dimethyltryptamines, which may act as systemic endogenous regulators of inflammation and immune homeostasis through the sigma-1 receptor. PMID:25171370

  20. Psychedelic N,N-dimethyltryptamine and 5-methoxy-N,N-dimethyltryptamine modulate innate and adaptive inflammatory responses through the sigma-1 receptor of human monocyte-derived dendritic cells.

    PubMed

    Szabo, Attila; Kovacs, Attila; Frecska, Ede; Rajnavolgyi, Eva

    2014-01-01

    The orphan receptor sigma-1 (sigmar-1) is a transmembrane chaperone protein expressed in both the central nervous system and in immune cells. It has been shown to regulate neuronal differentiation and cell survival, and mediates anti-inflammatory responses and immunosuppression in murine in vivo models. Since the details of these findings have not been elucidated so far, we studied the effects of the endogenous sigmar-1 ligands N,N-dimethyltryptamine (NN-DMT), its derivative 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and the synthetic high affinity sigmar-1 agonist PRE-084 hydrochloride on human primary monocyte-derived dendritic cell (moDCs) activation provoked by LPS, polyI:C or pathogen-derived stimuli to induce inflammatory responses. Co-treatment of moDC with these activators and sigma-1 receptor ligands inhibited the production of pro-inflammatory cytokines IL-1β, IL-6, TNFα and the chemokine IL-8, while increased the secretion of the anti-inflammatory cytokine IL-10. The T-cell activating capacity of moDCs was also inhibited, and dimethyltryptamines used in combination with E. coli or influenza virus as stimulators decreased the differentiation of moDC-induced Th1 and Th17 inflammatory effector T-cells in a sigmar-1 specific manner as confirmed by gene silencing. Here we demonstrate for the first time the immunomodulatory potential of NN-DMT and 5-MeO-DMT on human moDC functions via sigmar-1 that could be harnessed for the pharmacological treatment of autoimmune diseases and chronic inflammatory conditions of the CNS or peripheral tissues. Our findings also point out a new biological role for dimethyltryptamines, which may act as systemic endogenous regulators of inflammation and immune homeostasis through the sigma-1 receptor. PMID:25171370

  1. Phenotypic and functional activation of hyporesponsive KIRnegNKG2Aneg human NK-cell precursors requires IL12p70 provided by Poly(I:C)-matured monocyte-derived dendritic cells.

    PubMed

    Curran, Shane A; Romano, Emanuela; Kennedy, Michael G; Hsu, Katharine C; Young, James W

    2014-10-01

    A functionally responsive natural killer (NK)-cell repertoire requires the acquisition of inhibitory NKG2A and killer immunoglobulin-like receptors (KIR) through pathways that remain undefined. Functional donor NK cells expressing KIRs for non-self class I MHC ligands contribute to a positive outcome after allogeneic hematopoietic stem cell transplantation (alloHSCT) by targeting HLA-matched recipient leukemic cells. Insofar as circulating donor conventional dendritic cells (DC) reconstitute with comparable kinetics with donor NK cells after alloHSCT, we used hyporesponsive KIRnegNKG2Aneg precursor cells to evaluate how specific DC subtypes generate a functionally active NK-cell repertoire. Both monocyte-derived DCs (moDC) and Langerhans-type DCs (LC) induce KIRnegNKG2Aneg precursor cells to express the inhibitory receptors NKG2A and KIR, without requiring cell proliferation. Poly(I:C)-matured moDCs significantly augmented the expression of NKG2A, but not KIR, in an IL12p70-dependent manner. Although all DC-stimulated KIRnegNKG2Aneg cells were able to acquire cytolytic activity against class I MHC-negative targets, the ability to secrete IFNγ was restricted to cells that were stimulated by IL12p70-producing, poly(I:C)-matured moDCs. This critical ability of poly(I:C)-matured moDCs to provide IL12p70 to developing KIRnegNKG2Aneg precursors results in a dom4inant, multifunctional, NKG2Apos NK-cell population that is capable of both cytolysis and IFNγ production. Poly(I:C)-matured moDCs are, therefore, the most effective conventional DC subtype for generating a functionally competent NK-cell repertoire by an IL12p70-dependent mechanism. PMID:25023628

  2. Analysis of proteomic profiles and functional properties of human peripheral blood myeloid dendritic cells, monocyte-derived dendritic cells and the dendritic cell-like KG-1 cells reveals distinct characteristics

    PubMed Central

    2007-01-01

    Background Dendritic cells (DCs) are specialized antigen presenting cells that play a pivotal role in bridging innate and adaptive immune responses. Given the scarcity of peripheral blood myeloid dendritic cells (mDCs) investigators have used different model systems for studying DC biology. Monocyte-derived dendritic cells (moDCs) and KG-1 cells are routinely used as mDC models, but a thorough comparison of these cells has not yet been carried out, particularly in relation to their proteomes. We therefore sought to run a comparative study of the proteomes and functional properties of these cells. Results Despite general similarities between mDCs and the model systems, moDCs and KG-1 cells, our findings identified some significant differences in the proteomes of these cells, and the findings were confirmed by ELISA detection of a selection of proteins. This was particularly noticeable with proteins involved in cell growth and maintenance (for example, fibrinogen γ chain (FGG) and ubiquinol cytochrome c) and cell-cell interaction and integrity (for example, fascin and actin). We then examined the surface phenotype, cytokine profile, endocytic and T-cell-activation ability of these cells in support of the proteomic data, and obtained confirmatory evidence for differences in the maturation status and functional attributes between mDCs and the two DC models. Conclusion We have identified important proteomic and functional differences between mDCs and two DC model systems. These differences could have major functional implications, particularly in relation to DC-T cell interactions, the so-called immunological synapse, and, therefore, need to be considered when interpreting data obtained from model DC systems. PMID:17331236

  3. The abcEDCBA-Encoded ABC Transporter and the virB Operon-Encoded Type IV Secretion System of Brucella ovis Are Critical for Intracellular Trafficking and Survival in Ovine Monocyte-Derived Macrophages

    PubMed Central

    Macedo, Auricelio A.; Silva, Ana P. C.; Mol, Juliana P. S.; Costa, Luciana F.; Garcia, Luize N. N.; Araújo, Marcio S.; Martins Filho, Olindo A.; Paixão, Tatiane A.; Santos, Renato L.

    2015-01-01

    Brucella ovis infection is associated with epididymitis, orchitis and infertility in rams. Most of the information available on B. ovis and host cell interaction has been generated using murine macrophages or epithelial cell lines, but the interaction between B. ovis and primary ovine macrophages has not been studied. The aim of this study was to evaluate the role of the B. ovis abcEDCBA-encoded ABC transporter and the virB operon-encoded Type IV Secretion System (T4SS) during intracellular survival of B. ovis in ovine peripheral blood monocyte-derived macrophages. ΔabcBA and ΔvirB2 mutant strains were unable to survive in the intracellular environment when compared to the WT B. ovis at 48 hours post infection (hpi). In addition, these mutant strains cannot exclude the lysosomal marker LAMP1 from its vacuolar membrane, and their vacuoles do not acquire the endoplasmic reticulum marker calreticulin, which takes place in the WT B. ovis containing vacuole. Higher levels of nitric oxide production were observed in macrophages infected with WT B. ovis at 48 hpi when compared to macrophages infected with the ΔabcBA or ΔvirB2 mutant strains. Conversely, higher levels of reactive oxygen species were detected in macrophages infected with the ΔabcBA or ΔvirB2 mutant strains at 48 hpi when compared to macrophages infected with the WT strain. Our results demonstrate that B. ovis is able to persist and multiply in ovine macrophages, while ΔabcBA and ΔvirB2 mutations prevent intracellular multiplication, favor phagolysosome fusion, and impair maturation of the B. ovis vacuole towards an endoplasmic reticulum-derived compartment. PMID:26366863

  4. Accessory cells with a veiled morphology and movement pattern generated from monocytes after avoidance of plastic adherence and of NADPH oxidase activation. A comparison with GM-CSF/IL-4-induced monocyte-derived dendritic cells.

    PubMed

    Ruwhof, Cindy; Canning, Martha O; Grotenhuis, Kristel; de Wit, Harm J; Florencia, Zenovia Z; de Haan-Meulman, Meeny; Drexhage, Hemmo A

    2002-07-01

    Veiled cells (VC) present in afferent lymph transport antigen from the periphery to the draining lymph nodes. Although VC in lymph form a heterogeneous population, some of the cells clearly belong on morphological grounds to the Langerhans cell (LC)/ dendritic cell (DC) series. Here we show that culturing monocytes for 24 hrs while avoiding plastic adherence (polypropylene tubes) and avoiding the activation of NADPH oxidase (blocking agents) results in the generation of a population of veiled accessory cells. The generated VC were actively moving cells like lymph-borne VC in vivo. The monocyte (mo)-derived VC population existed of CD14(dim/-) and CD14(brighT) cells. Of these the CD14(dim/-) VC were as good in stimulating allogeneic T cell proliferation as immature DC (iDC) obtained after one week of adherent culture of monocytes in granulocyte-macrophage-colony stimulating factor (GM-CSF)/interleukin (IL)-4. This underscores the accessory cell function of the mo-derived CD14(dim/-) VC. Although the CD14(dim/-)VC had a modest expression of the DC-specific marker CD83 and were positive for S100, expression of the DC-specific markers CD1a, Langerin, DC-SIGN, and DC-LAMP were absent. This indicates that the here generated CD14(dim/-) VC can not be considered as classical LC/DC. It was also impossible to turn the CD14(dim/-) mo-derived VC population into typical DC by culture for one week in GM-CSF/IL-4 or LPS. In fact the cells died tinder such circumstances, gaining some macrophage characteristics before dying. The IL-12 production from mo-derived CD14(dim/-) VC was lower, whereas the production of IL-10 was higher as compared to iDC. Consequently the T cells that were stimulated by these mo-derived VC produced less IFN-gamma as compared with T cells stimulated by iDC. Our data indicate that it is possible to rapidly generate a population of CD14(dim/-) veiled accessory cells from monocytes. The marker pattern and cytokine production of these VC indicate that this

  5. Dysregulation of lipid metabolism in Tangier monocyte-derived macrophages.

    PubMed

    Schmitz, G; Fischer, H; Beuck, M; Hoecker, K P; Robenek, H

    1990-01-01

    The cellular defect in Tangier mononuclear phagocytes (MNP) was shown to be associated with significant abnormalities in cellular phospholipid, triglyceride, and cholesteryl ester metabolism by using various radiolabeled precursors (32Pi, 3H-serine, 3H-choline, 14C-acetate, and 14C-oleic acid). Tangier MNP expressed increased rates of synthesis for phospholipids (twofold), triglycerides (fivefold), and cholesteryl esters (threefold) as compared to normal MNP when incubated in McCoy's medium containing 0.2% human serum albumin. The turnover rate of cellular phospholipids was also enhanced, while the turnover rates for triglycerides and cholesteryl esters were normal, thus leading to the accumulation of a larger pool of labeled triglycerides and cholesteryl esters in Tangier MNP. The individual phospholipid classes, phosphatidylcholine, sphingomyelin, phosphatidylethanolamine, and phosphatidylserine were similarly affected. Cholesterol loading led to approximately 30% down-regulation of phospholipid synthesis in normal cells, but Tangier MNP showed a smaller response. When nonloaded normal MNP were exposed to high density lipoprotein3 (HDL3), they diminished cellular cholesterol esterification mediated by acyl-CoA:cholesterol acyltransferase (ACAT); in Tangier MNP, ACAT activity increased in the presence of HDL3. When cholesterol-loaded normal and Tangier MNP were treated with HDL3, an up-regulation of phospholipid synthesis was observed in both cell types, but Tangier MNP showed a smaller response. We conclude that the defect in Tangier disease, which we recently described as a "disorder of intracellular traffic" (Schmitz et al. Proc Natl Acad Sci USA 1985;82:6305-6309), is associated with a dysregulation of cellular lipid metabolism, leading to an overproduction of triglycerides and esterified cholesterol and to enhanced synthesis and catabolism of phospholipids. PMID:2244850

  6. Bovine viral diarrhea virus modulations of monocyte derived macrophages

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Bovine viral diarrhea virus (BVDV) is a single stranded, positive sense RNA virus and is the causative agent of bovine viral diarrhea (BVD). Disease can range from persistently infected (PI) animals displaying no clinical symptoms of disease to an acute, severe disease. Presently, limited studies ha...

  7. Bovine Viral Diarrhea Virus Modulation of Monocyte Derived Macrophage

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Bovine Viral Diarrhea Virus (BVDV) is a single stranded, positive sense virus of the Flaviviridae family and is the causative agent of the disease known as Bovine Viral Diarrhea (BVD). Disease can range from persistently infected (PI) animals displaying no clinical symptoms of disease to an acute, s...

  8. von Willebrand factor binds to the surface of dendritic cells and modulates peptide presentation of factor VIII

    PubMed Central

    Sorvillo, Nicoletta; Hartholt, Robin B.; Bloem, Esther; Sedek, Magdalena; Brinke, Anja ten; van der Zwaan, Carmen; van Alphen, Floris P.; Meijer, Alexander B.; Voorberg, Jan

    2016-01-01

    It has been proposed that von Willebrand factor might affect factor VIII immunogenicity by reducing factor VIII uptake by antigen presenting cells. Here we investigate the interaction of recombinant von Willebrand factor with immature monocyte-derived dendritic cells using flow cytometry and confocal microscopy. Surprisingly, von Willebrand factor was not internalized by immature dendritic cells, but remained bound to the cell surface. As von Willebrand factor reduces the uptake of factor VIII, we investigated the repertoire of factor VIII presented peptides when in complex with von Willebrand factor. Interestingly, factor VIII-derived peptides were still abundantly presented on major histocompatibility complex class II molecules, even though a reduction of factor VIII uptake by immature dendritic cells was observed. Inspection of peptide profiles from 5 different donors showed that different core factor VIII peptide sequences were presented upon incubation with factor VIII/von Willebrand factor complex when compared to factor VIII alone. No von Willebrand factor peptides were detected when immature dendritic cells were pulsed with different concentrations of von Willebrand factor, confirming lack of von Willebrand factor endocytosis. Several von Willebrand factor derived peptides were recovered when cells were pulsed with von Willebrand factor/factor VIII complex, suggesting that factor VIII promotes endocytosis of small amounts of von Willebrand factor by immature dendritic cells. Taken together, our results establish that von Willebrand factor is poorly internalized by immature dendritic cells. We also show that von Willebrand factor modulates the internalization and presentation of factor VIII-derived peptides on major histocompatibility complex class II. PMID:26635035

  9. Transforming growth factor alpha may be a physiological regulator of liver regeneration by means of an autocrine mechanism.

    PubMed Central

    Mead, J E; Fausto, N

    1989-01-01

    We investigated whether transforming growth factor alpha (TGF-alpha) is involved in hepatocyte growth responses both in vivo and in culture. During liver regeneration after partial hepatectomy in rats, TGF-alpha mRNA increased; it reached a maximum (approximately 9-fold higher than normal) at the peak of DNA synthesis. The message and the peptide were localized in hepatocytes and found in higher amounts in hepatocytes obtained from regenerating liver. TGF-alpha caused a 13-fold elevation of DNA synthesis in hepatocytes in primary culture and was slightly more effective than epidermal growth factor. TGF-beta blocked TGF-alpha stimulation when added either simultaneously with TGF-alpha or a day later. TGF-alpha message increased in hepatocytes stimulated to undergo DNA synthesis by TGF-alpha or epidermal growth factor, and the peptide was detected in the culture medium by RIA. In the regenerating liver, the increase in TGF-alpha mRNA during the first day after partial hepatectomy coincided with an increase in epidermal growth factor/TGF-alpha receptor mRNA and a decrease (already reported) in the number of these receptors. We conclude that TGF-alpha may function as a physiological inducer of hepatocyte DNA synthesis during liver regeneration by means of an autocrine mechanism and that its stimulatory effects in this growth process are balanced by the inhibitory action of TGF-beta 1. Images PMID:2922399

  10. Human lung-resident macrophages express CB1 and CB2 receptors whose activation inhibits the release of angiogenic and lymphangiogenic factors.

    PubMed

    Staiano, Rosaria I; Loffredo, Stefania; Borriello, Francesco; Iannotti, Fabio Arturo; Piscitelli, Fabiana; Orlando, Pierangelo; Secondo, Agnese; Granata, Francescopaolo; Lepore, Maria Teresa; Fiorelli, Alfonso; Varricchi, Gilda; Santini, Mario; Triggiani, Massimo; Di Marzo, Vincenzo; Marone, Gianni

    2016-04-01

    Macrophages are pivotal effector cells in immune responses and tissue remodeling by producing a wide spectrum of mediators, including angiogenic and lymphangiogenic factors. Activation of cannabinoid receptor types 1 and 2 has been suggested as a new strategy to modulate angiogenesis in vitro and in vivo. We investigated whether human lung-resident macrophages express a complete endocannabinoid system by assessing their production of endocannabinoids and expression of cannabinoid receptors. Unstimulated human lung macrophage produce 2-arachidonoylglycerol,N-arachidonoyl-ethanolamine,N-palmitoyl-ethanolamine, andN-oleoyl-ethanolamine. On LPS stimulation, human lung macrophages selectively synthesize 2-arachidonoylglycerol in a calcium-dependent manner. Human lung macrophages express cannabinoid receptor types 1 and 2, and their activation induces ERK1/2 phosphorylation and reactive oxygen species generation. Cannabinoid receptor activation by the specific synthetic agonists ACEA and JWH-133 (but not the endogenous agonist 2-arachidonoylglycerol) markedly inhibits LPS-induced production of vascular endothelial growth factor-A, vascular endothelial growth factor-C, and angiopoietins and modestly affects IL-6 secretion. No significant modulation of TNF-α or IL-8/CXCL8 release was observed. The production of vascular endothelial growth factor-A by human monocyte-derived macrophages is not modulated by activation of cannabinoid receptor types 1 and 2. Given the prominent role of macrophage-assisted vascular remodeling in many tumors, we identified the expression of cannabinoid receptors in lung cancer-associated macrophages. Our results demonstrate that cannabinoid receptor activation selectively inhibits the release of angiogenic and lymphangiogenic factors from human lung macrophage but not from monocyte-derived macrophages. Activation of cannabinoid receptors on tissue-resident macrophages might be a novel strategy to modulate macrophage-assisted vascular remodeling

  11. Survival of Mycobacterium avium subsp. paratuberculosis in bovine monocyte-derived macrophages

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Johne’s disease is a significant problem in many North American cattle herds. The efficacy of currently available vaccines is questionable. There is a need to develop efficacious vaccines and strains of Mycobacterium avium subsp. paratuberculosis (MAPTB) that could serve as potential candidates for ...

  12. Human SOCS1 Controls Immunostimulatory Activity of Monocyte-derived Dendritic Cells

    PubMed Central

    Hong, Bangxing; Ren, Wenhong; Song, Xiao-Tong; Evel-Kabler, Kevin; Chen, Si-Yi; Huang, Xue F

    2009-01-01

    Dendritic cell (DC)-based tumor vaccines have only achieved limited clinical efficacy, underscoring the limitation of stimulatory strategies to elicit effective cytotoxic T lymphocyte (CTL) responses against self tumor-associated antigens. Here we investigate the role of human suppressor of cytokine signaling (SOCS) 1, a feedback inhibitor of the JAK/STAT signaling pathway, in regulating antigen presentation by human DCs. We find that human SOCS1-silenced DCs have an enhanced stimulatory ability to prime self antigen-specific CTLs in vitro and in an SCID-hu mouse model. Human CTLs activated by SOCS1-silenced DCs, but not wild-type DCs, have an active lytic activity to natural antigen-expressing tumor cells. We further find that the capacity of human DCs to prime CTLs is likely controlled by SOCS1 restricted production and signaling of proinflammatory cytokines such as IL-12. These results indicate a critical role of human SOCS1 in negatively regulating the immunostimulatory capacity of DCs and imply a translational potential of this alternative, SOCS1 silencing strategy to develop effective DC vaccines. PMID:19789342

  13. The effect of human immunodeficiency virus-1 on monocyte-derived dendritic cell maturation and function

    PubMed Central

    Fairman, P; Angel, J B

    2012-01-01

    Dendritic cells (DC) are mediators of the adaptive immune response responsible for antigen presentation to naive T cells in secondary lymph organs. Human immunodeficiency virus (HIV-1) has been reported to inhibit the maturation of DC, but a clear link between maturation and function has not been elucidated. To understand further the effects of HIV-1 on DC maturation and function, we expanded upon previous investigations and assessed the effects of HIV-1 infection on the expression of surface molecules, carbohydrate endocytosis, antigen presentation and lipopolysaccharide (LPS) responsiveness over the course of maturation. In vitro infection with HIV-1 resulted in an increase in the expression of DC-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) as well as decreases in maturation-induced CCR7 and major histocompatibility complex (MHC)-II expression. Retention of endocytosis that normally occurs with DC maturation as well as inhibition of antigen presentation to CD8+ T cells was also observed. Mitogen-activated protein kinase (MAPK) responsiveness to LPS as measured by phosphorylation of p38, c-Jun N-terminal kinase (JNK) and extracellular-regulated kinase (ERK)1/2 was not affected by HIV-1 infection. In summary, in-vitro HIV-1 impairs DC maturation, as defined by cell surface protein expression, with selective alterations in mature DC function. Understanding the mechanisms of DC dysfunction in HIV infection will provide further insight into HIV immune pathogenesis. PMID:22943206

  14. Characterization of the porcine monocyte-derived cell lines Cdelta2- and Cdelta2+

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Cell lines Cdelta2- and Cdelta2+ were developed from monocytes obtained from a 10-month-old, crossbred, female pig at the U.S. Meat Animal Research Center, Clay Center, NE. These cells have macrophage morphology, stain positively for alpha-naphthyl esterase and negatively for peroxidase. Additiona...

  15. Combination strategies to enhance the potency of monocyte-derived dendritic cell-based cancer vaccines.

    PubMed

    Fecek, Ronald J; Storkus, Walter J

    2016-10-01

    Dendritic cells (DCs) are potent inducers of adaptive immunity and their clinical use in cancer vaccine formulations remains an area of active translational and clinical investigation. Although cancer vaccines applied as monotherapies have had a modest history of clinical success, there is great enthusiasm for novel therapeutic strategies combining DC-based cancer vaccines with agents that 'normalize' immune function in the tumor microenvironment (TME). Broadly, these combination vaccines are designed to antagonize/remove immunosuppressive networks within the TME that serve to limit the antitumor action of vaccine-induced T cells and/or to condition the TME to facilitate the recruitment and optimal function and durability of vaccine-induced T cells. Such combination regimens are expected to dramatically enhance the clinical potency of DC-based cancer vaccine platforms. PMID:27605069

  16. Radiation effects on cultured human monocytes and on monocyte-derived macrophages

    SciTech Connect

    Buescher, E.S.; Gallin, J.I.

    1984-06-01

    Prior to administration, leukocyte transfusions are commonly irradiated with up to 5,000 R to eliminate lymphocytes and thereby prevent graft-versus-host disease in the recipient. It has been widely believed that phagocytes are resistant to this irradiation. In a recent report, it was noted that phagocyte oxidative metabolism was compromised during preparation of white cells for transfusion. As part of the effort to examine the basis for this inhibition of phagocyte function during white cell preparation, an assessment was made of the effects of irradiation on the long-lived monocytes that have been shown to persist at inflammatory foci posttransfusion. Human monocytes were irradiated for up to 3 min, receiving 2,500-5,000 R. This irradiation damaged human monocytes, significantly decreasing their in vitro survival for the first 3 wk of culture, and growth as assessed by two-dimensional cell size measurements during the first 2 wk of culture. Despite smaller cell size, total cell protein was significantly increased over time in irradiated cultures. Extracellular release of lysozyme and beta-glucuronidase per cell was not affected by irradiation, but extracellular lactate dehydrogenase (LDH) release was significantly increased after irradiation. Irradiated monocytes killed Listeria monocytogenes at a slower rate than the nonirradiated controls. Thus, the data indicate that irradiation in doses used to prevent graft-versus-host disease in leukocyte transfusion recipients has a deleterious effect on in vitro human monocyte survival and function.

  17. Development and characterization of two porcine monocyte-derived macrophage cell lines

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Cell lines Cdelta2+ and Cdelta2- were developed from monocytes obtained from a 10-month-old, crossbred, female pig. These cells morphologically resembled macrophages, stained positively for a-naphthyl esterase and negatively for peroxidase. The cell lines were bactericidal and highly phagocytic. ...

  18. Chrysin suppresses human CD14(+) monocyte-derived dendritic cells and ameliorates experimental autoimmune encephalomyelitis.

    PubMed

    Zhang, Kai; Ge, Zhenzhen; Xue, Zhenyi; Huang, Wenjing; Mei, Mei; Zhang, Qi; Li, Yan; Li, Wen; Zhang, Zhihui; Zhang, Zimu; Zhang, Lijuan; Wang, Huafeng; Cai, Jinzhen; Yao, Zhi; Zhang, Rongxin; Da, Yurong

    2015-11-15

    Chrysin, a naturally flavonoid of plant, has various biological activities. However, the effects of chrysin on dendritic cells (DCs) and multiple sclerosis (MS) remain unknown. In this study, we demonstrate that chrysin inhibited human DC differentiation, maturation, function and the expression of the Th1 cells polarizing cytokines IFN-γ and IL-12p35 form DCs. In addition, chrysin ameliorated experimental autoimmune encephalomyelitis (EAE), an animal model of MS, by reducing CNS inflammation and demyelination. Furthermore, chrysin suppressed DCs and Th1 cells in the EAE mice. Taken together, chrysin exerts anti-inflammatory and immune suppressive effects, and suggests a possible therapeutic application of chrysin in MS. PMID:26531689

  19. NFκB2/p100 is a key factor for endotoxin tolerance in human monocytes: a demonstration using primary human monocytes from patients with sepsis.

    PubMed

    Cubillos-Zapata, Carolina; Hernández-Jiménez, Enrique; Toledano, Víctor; Esteban-Burgos, Laura; Fernández-Ruíz, Irene; Gómez-Piña, Vanesa; Del Fresno, Carlos; Siliceo, María; Prieto-Chinchiña, Patricia; Pérez de Diego, Rebeca; Boscá, Lisardo; Fresno, Manuel; Arnalich, Francisco; López-Collazo, Eduardo

    2014-10-15

    Endotoxin tolerance (ET) is a state of reduced responsiveness to endotoxin stimulation after a primary bacterial insult. This phenomenon has been described in several pathologies, including sepsis, in which an endotoxin challenge results in reduced cytokine production. In this study, we show that the NFκ L chain enhancer of activated B cells 2 (NFκB2)/p100 was overexpressed and accumulated in a well-established in vitro human monocyte model of ET. The p100 accumulation in these cells inversely correlated with the inflammatory response after LPS stimulation. Knocking down NFκB2/p100 using small interfering RNA in human monocytes further indicated that p100 expression is a crucial factor in the progression of ET. The monocytes derived from patients with sepsis had high levels of p100, and a downregulation of NFκB2/p100 in these septic monocytes reversed their ET status. PMID:25225662

  20. Involvement of interleukin-8, vascular endothelial growth factor, and basic fibroblast growth factor in tumor necrosis factor alpha-dependent angiogenesis.

    PubMed Central

    Yoshida, S; Ono, M; Shono, T; Izumi, H; Ishibashi, T; Suzuki, H; Kuwano, M

    1997-01-01

    Tumor necrosis factor alpha (TNF-alpha) is a macrophage/monocyte-derived polypeptide which modulates the expression of various genes in vascular endothelial cells and induces angiogenesis. However, the underlying mechanism by which TNF-alpha mediates angiogenesis is not completely understood. In this study, we assessed whether TNF-alpha-induced angiogenesis is mediated through TNF-alpha itself or indirectly through other TNF-alpha-induced angiogenesis-promoting factors. Cellular mRNA levels of interleukin-8 (IL-8), vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and their receptors were increased after the treatment of human microvascular endothelial cells with TNF-alpha (100 U/ml). TNF-alpha-dependent tubular morphogenesis in vascular endothelial cells was inhibited by the administration of anti-IL-8, anti-VEGF, and anti-bFGF antibodies, and coadministration of all three antibodies almost completely abrogated tubular formation. Moreover, treatment with Sp1, NF-kappaB, and c-Jun antisense oligonucleotides inhibited TNF-alpha-dependent tubular morphogenesis by microvascular endothelial cells. Administration of a NF-kappaB antisense oligonucleotide almost completely inhibited TNF-alpha-dependent IL-8 production and partially abrogated TNF-alpha-dependent VEGF production, and an Sp1 antisense sequence partially inhibited TNF-alpha-dependent production of VEGF. A c-Jun antisense oligonucleotide significantly inhibited TNF-alpha-dependent bFGF production but did not affect the production of IL-8 and VEGF. Administration of an anti-IL-8 or anti-VEGF antibody also blocked TNF-alpha-induced neovascularization in the rabbit cornea in vivo. Thus, angiogenesis by TNF-alpha appears to be modulated through various angiogenic factors, both in vitro and in vivo, and this pathway is controlled through paracrine and/or autocrine mechanisms. PMID:9199336

  1. Inhibition of Nuclear Factor-Kappa B Activation Decreases Survival of Mycobacterium tuberculosis in Human Macrophages

    PubMed Central

    Chmura, Kathryn; Ovrutsky, Alida R.; Su, Wen-Lin; Griffin, Laura; Pyeon, Dohun; McGibney, Mischa T.; Strand, Matthew J.; Numata, Mari; Murakami, Seiji; Gaido, Loretta; Honda, Jennifer R.; Kinney, William H.; Oberley-Deegan, Rebecca E.; Voelker, Dennis R.; Ordway, Diane J.; Chan, Edward D.

    2013-01-01

    Nuclear factor-kappa B (NFκB) is a ubiquitous transcription factor that mediates pro-inflammatory responses required for host control of many microbial pathogens; on the other hand, NFκB has been implicated in the pathogenesis of other inflammatory and infectious diseases. Mice with genetic disruption of the p50 subunit of NFκB are more likely to succumb to Mycobacterium tuberculosis (MTB). However, the role of NFκB in host defense in humans is not fully understood. We sought to examine the role of NFκB activation in the immune response of human macrophages to MTB. Targeted pharmacologic inhibition of NFκB activation using BAY 11-7082 (BAY, an inhibitor of IκBα kinase) or an adenovirus construct with a dominant-negative IκBα significantly decreased the number of viable intracellular mycobacteria recovered from THP-1 macrophages four and eight days after infection. The results with BAY were confirmed in primary human monocyte-derived macrophages and alveolar macrophages. NFκB inhibition was associated with increased macrophage apoptosis and autophagy, which are well-established killing mechanisms of intracellular MTB. Inhibition of the executioner protease caspase-3 or of the autophagic pathway significantly abrogated the effects of BAY. We conclude that NFκB inhibition decreases viability of intracellular MTB in human macrophages via induction of apoptosis and autophagy. PMID:23634218

  2. Inhibition of nuclear factor-kappa B activation decreases survival of Mycobacterium tuberculosis in human macrophages.

    PubMed

    Bai, Xiyuan; Feldman, Nicole E; Chmura, Kathryn; Ovrutsky, Alida R; Su, Wen-Lin; Griffin, Laura; Pyeon, Dohun; McGibney, Mischa T; Strand, Matthew J; Numata, Mari; Murakami, Seiji; Gaido, Loretta; Honda, Jennifer R; Kinney, William H; Oberley-Deegan, Rebecca E; Voelker, Dennis R; Ordway, Diane J; Chan, Edward D

    2013-01-01

    Nuclear factor-kappa B (NFκB) is a ubiquitous transcription factor that mediates pro-inflammatory responses required for host control of many microbial pathogens; on the other hand, NFκB has been implicated in the pathogenesis of other inflammatory and infectious diseases. Mice with genetic disruption of the p50 subunit of NFκB are more likely to succumb to Mycobacterium tuberculosis (MTB). However, the role of NFκB in host defense in humans is not fully understood. We sought to examine the role of NFκB activation in the immune response of human macrophages to MTB. Targeted pharmacologic inhibition of NFκB activation using BAY 11-7082 (BAY, an inhibitor of IκBα kinase) or an adenovirus construct with a dominant-negative IκBα significantly decreased the number of viable intracellular mycobacteria recovered from THP-1 macrophages four and eight days after infection. The results with BAY were confirmed in primary human monocyte-derived macrophages and alveolar macrophages. NFκB inhibition was associated with increased macrophage apoptosis and autophagy, which are well-established killing mechanisms of intracellular MTB. Inhibition of the executioner protease caspase-3 or of the autophagic pathway significantly abrogated the effects of BAY. We conclude that NFκB inhibition decreases viability of intracellular MTB in human macrophages via induction of apoptosis and autophagy. PMID:23634218

  3. Human testis cytosol and ovarian follicular fluid contain high amounts of interleukin-1-like factor(s).

    PubMed

    Khan, S A; Schmidt, K; Hallin, P; Di Pauli, R; De Geyter, C; Nieschlag, E

    1988-08-01

    Human testicular cytosol and ovarian follicular fluid were analyzed for the presence of interleukin-1 (IL-1)-like factors. Both the follicular fluid and testis cytosol preparations exhibited significant IL-1-like activity as determined by the murine thymocyte proliferation bioassay. The dose-response lines obtained with the gonadal preparations were parallel to each other and to those obtained with monocyte-derived IL-1 and the activity of the gonadal IL-1 could be neutralized by specific IL-1 antibodies. After gel chromatography of human follicular fluid (hFF) and human testis cytosol (hTC) proteins, IL-1 activity was found in the molecular weight region between 30 and 50 kilodaltons (kDa). Chromatofocusing of IL-1 from hFF and hTC revealed that the major part of IL-1 in both cases exhibited similar charge properties (pI less than 6.0). However, two extra peaks (pI 7.0 and greater than 9.0, respectively) were observed in hFF preparations. After isoelectrofocusing (IEF), IL-1 activity of hFF was also found in two different pH regions; a broad area of activity was localized between pH 5.5 and 7.0, while a sharp peak was observed with an approximate pI value of 9.5. Re-chromatofocusing or IEF of alkaline IL-1-like activity resulted in a heterogeneous profile of IL-1-like activity suggesting that the alkaline material may represent either a precursor or an aggregated form of the acidic IL-1. None of the IL-1 peaks obtained from hFF or hTC exhibited IL-2 activity as assessed in a specific IL-2 bioassay. The results of the present study indicate that both gonads may produce high amounts of IL-1-like factor(s) which might play a regulatory role in normal gonadal function. PMID:3264798

  4. Regulation of monocyte MMP-9 production by TNF-alpha and a tumour-derived soluble factor (MMPSF).

    PubMed Central

    Leber, T. M.; Balkwill, F. R.

    1998-01-01

    The matrix metalloprotease MMP-9 localizes to tumour-associated macrophages in human ovarian cancer but little is known of its regulation. Co-culture of human ovarian cancer cells (PEO-1) and a monocytic cell line (THP-1) led to production of 92-kDa proMMP-9. PEO-1-conditioned medium (CM) also stimulated THP-1 cells or isolated peripheral blood monocytes to produce proMMP-9. Expression of TIMP-1, however, remained unaffected. There was evidence that tumour necrosis factor alpha (TNF-alpha) was involved in tumour-stimulated monocytic proMMP-9 production. Antibody to TNF-alpha inhibited proMMP-9 production, and synthesis of TNF-alpha mRNA and protein preceded proMMP-9 release. In addition, the synthetic matrix metalloprotease inhibitor (MMPI) BB-2116, which blocks TNF-alpha shedding, inhibited proMMP-9 release in the co-cultures and from CM-stimulated monocytic cells. Further experiments suggested that the stimulating factor present in CM was not TNF-alpha, but acted synergistically with autocrine monocyte-derived TNF-alpha to release monocytic proMMP-9. Thus, ovarian cancer cells can stimulate monocytic cells in vitro to make proMMP-9 without affecting the expression of its inhibitor TIMP-1. This induction is mediated via a soluble factor (provisionally named MMPSF) that requires synergistic action of autocrine or paracrine TNF-alpha. Images Figure 1 Figure 4 Figure 7 PMID:9743290

  5. Glucose levels affect LL-37 expression in monocyte-derived macrophages altering the Mycobacterium tuberculosis intracellular growth control.

    PubMed

    Montoya-Rosales, Alejandra; Castro-Garcia, Pamela; Torres-Juarez, Flor; Enciso-Moreno, Jose Antonio; Rivas-Santiago, Bruno

    2016-08-01

    Diabetes mellitus (DM)-2 patients have an increased susceptibility to develop pulmonary tuberculosis; this is partly due to the impairment of the innate immunity because of their higher glucose concentrations. In the present study, we determined the effect of the glucose concentrations in the LL-37 expression in infected and non-infected macrophages. Our results showed that the increasing glucose concentrations correlates with the low cathelicidin expression in non-infected cells, however in Mycobacterium tuberculosis infected cells, LL-37 expression was substantially increased in higher glucose concentrations, nevertheless the mycobacterial burden also increased, this phenomena can be associated with the cathelicidin immunomodulatory activity. Further evaluation for LL-37 needs to be done to determine whether this peptide can be used as a biomarker of tuberculosis progression in DM2 patients. PMID:27263098

  6. Effects of inactivated porcine epidemic diarrhea virus on porcine monocyte-derived dendritic cells and intestinal dendritic cells.

    PubMed

    Gao, Qi; Zhao, Shanshan; Qin, Tao; Yin, Yinyan; Yu, Qinghua; Yang, Qian

    2016-06-01

    Porcine epidemic diarrhea (PED) is a serious infection in neonatal piglets. As the causative agent of PED, porcine epidemic diarrhea virus (PEDV) results in acute diarrhea and dehydration with high mortality rates in swine. Dendritic cells (DCs) are highly effective antigen-presenting cells to uptake and present viral antigens to T cells, which then initiate a distinct immune response. In this study, our results show that the expression of Mo-DCs surface markers such as SWC3a(+)CD1a(+), SWC3a(+)CD80/86(+) and SWC3a(+)SLA-II-DR(+) is increased after incubation with UV-PEDV for 24h. Mo-DCs incubated with UV-PEDV produce higher levels of IL-12 and INF-γ compared to mock-infected Mo-DCs. Interactions between Mo-DCs and UV-PEDV significantly stimulate T-cell proliferation in vitro. Consistent with these results, there is an enhancement in the ability of porcine intestinal DCs to activate T-cell proliferation in vivo. We conclude that UV-PEDV may be a useful and safe vaccine to trigger adaptive immunity. PMID:27234553

  7. Monocyte-derived macrophage assisted breast cancer cell invasion as a personalized, predictive metric to score metastatic risk

    PubMed Central

    Park, Keon-Young; Li, Gande; Platt, Manu O.

    2015-01-01

    Patient-to-patient variability in breast cancer progression complicates clinical treatment decisions. Of women undergoing prophylactic mastectomies, many may not have progressed to indolent forms of disease and could have benefited from milder, localized therapy. Tumor associated macrophages contribute significantly to tumor invasion and metastasis, with cysteine cathepsin proteases as important contributors. Here, a method is demonstrated by which variability in macrophage expression of cysteine cathepsins, their inhibitor cystatin C, and kinase activation can be used to train a multivariate model and score patients for invasion risk. These enzymatic profiles were used to predict macrophage-assisted MCF-7 breast cancer cell invasion in the trained computational model. To test these predictions, a priori, signals from monocytes isolated from women undergoing mastectomies were input to score their cancer invasion potential in a patient-specific manner, and successfully predicted that patient monocytes with highest predicted invasion indices matched those with more invasive initial diagnoses of the nine patients tested. Together this establishes proof-of-principle that personalized information acquired from minimally invasive blood draws may provide useful information to inform oncologists and patients of invasive/metastatic risk, helping to make decisions regarding radical mastectomy or milder, conservative treatments to save patients from hardship and surgical recovery. PMID:26349896

  8. Screening of Mycobacterium avium subsp. paratuberculosis mutants for attenuation in a bovine monocyte-derived macrophage model

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Vaccination remains a major tool for prevention and progression of Johne’s disease, a chronic enteritis of ruminants worldwide. Currently there is only one licensed vaccine within the United States and two vaccines licensed internationally against Johne’s disease. All licensed vaccines reduce fecal...

  9. Mesenchymal Stromal Cell-Like Cells Set the Balance of Stimulatory and Inhibitory Signals in Monocyte-Derived Dendritic Cells.

    PubMed

    Bacskai, Ildikó; Mázló, Anett; Kis-Tóth, Katalin; Szabó, Attila; Panyi, György; Sarkadi, Balázs; Apáti, Ágota; Rajnavölgyi, Éva

    2015-08-01

    The major reservoir of human multipotent mesenchymal stem/stromal cells (MSCs) is the bone marrow (BM) with the capability to control hematopoietic stem cell development. The regenerative potential of MSCs is associated with enhanced endogenous repair and healing mechanisms that modulate inflammatory responses. Our previous results revealed that MSC-like (MSCl) cells derived from pluripotent human embryonic stem cells resemble BM-derived MSCs in morphology, phenotype, and differentiating potential. In this study, we investigated the effects of MSCl cells on the phenotype and functions of dendritic cells (DCs). To assess how antiviral immune responses could be regulated by intracellular pattern recognition receptors of DCs in the presence of MSCl cells, we activated DCs with the specific ligands of retinoic acid-inducible gene-I (RIG-I) helicases and found that activated DCs cocultured with MSCl cells exhibited reduced expression of CD1a and CD83 cell surface molecules serving as phenotypic indicators of DC differentiation and activation, respectively. However, RIG-I-mediated stimulation of DCs through specific ligands in the presence of MSCl cells resulted in significantly higher expression of the costimulatory molecules, CD80 and CD86, than in the presence of BM-MSCs. In line with these results, the concentration of IL-6, IL-10, and CXCL8 was increased in the supernatant of the DC-MSCl cocultures, while the secretion of TNF-α, CXCL10, IL-12, and IFNγ was reduced. Furthermore, the concerted action of mechanisms involved in the regulation of DC migration resulted in the blockade of cell migration, indicating altered DC functionality mediated by MSCl cell-derived signals and mechanisms resulting in a suppressive microenvironment. PMID:25808140

  10. Bjcul, a snake venom lectin, modulates monocyte-derived macrophages to a pro-inflammatory profile in vitro.

    PubMed

    Dias-Netipanyj, M F; Boldrini-Leite, L M; Trindade, E S; Moreno-Amaral, A N; Elifio-Esposito, S

    2016-06-01

    Macrophages are cells of high plasticity and can act in different ways to ensure that the appropriate immune response remains controlled. This study shows the effects of the C-type Bothrops jararacussu venom lectin (BJcuL) on the activation of human macrophages derived from the U937 cell line. BJcuL binds on the cell surface, and this event is inhibited by its specific carbohydrate. It induced phagocytosis and production of H2O2, and expression of antigen presentation molecules. It also enhanced the production of TNF-α, GM-CSF and IL-6 by macrophages and indirectly induced T cells to an increased production of TNF-α, IFN-γ and IL-6 in the presence of LPS. Our results suggest that BJcuL can modulate macrophage functional activation towards an M1 state. PMID:26944802

  11. Comparative analysis of signature genes in PRRSV-infected porcine monocyte-derived dendritic cells at differential activation statuses

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Activation statuses of monocytic cells including monocytes, macrophages and dendritic cells (DCs) are critically important for antiviral immunity. In particular, some devastating viruses, including porcine reproductive and respiratory syndrome virus (PRRSV), are capable of directly infecting these c...

  12. Plasmacytoid, conventional, and monocyte-derived dendritic cells undergo a profound and convergent genetic reprogramming during their maturation

    PubMed Central

    Vu Manh, Thien-Phong; Alexandre, Yannick; Baranek, Thomas; Crozat, Karine; Dalod, Marc

    2013-01-01

    DCs express receptors sensing microbial, danger or cytokine signals, which when triggered in combination drive DC maturation and functional polarization. Maturation was proposed to result from a discrete number of modifications in conventional DCs (cDCs), in contrast to a cell-fate conversion in plasmacytoid DCs (pDCs). cDC maturation is generally assessed by measuring cytokine production and membrane expression of MHC class II and co-stimulation molecules. pDC maturation complexity was demonstrated by functional genomics. Here, pDCs and cDCs were shown to undergo profound and convergent changes in their gene expression programs in vivo during viral infection. This observation was generalized to other stimulation conditions and DC subsets, by public microarray data analyses, PCR confirmation of selected gene expression profiles, and gene regulatory sequence bioinformatics analyses. Thus, maturation is a complex process similarly reshaping all DC subsets, including through the induction of a core set of NF-κB- or IFN-stimulated genes irrespective of stimuli. PMID:23553052

  13. Monocyte-Derived Dendritic Cells Exhibit Increased Levels of Lysosomal Proteolysis as Compared to Other Human Dendritic Cell Populations

    PubMed Central

    McCurley, Nathanael; Mellman, Ira

    2010-01-01

    Background Fine control of lysosomal degradation for limited processing of internalized antigens is a hallmark of professional antigen presenting cells. Previous work in mice has shown that dendritic cells (DCs) contain lysosomes with remarkably low protease content. Combined with the ability to modulate lysosomal pH during phagocytosis and maturation, murine DCs enhance their production of class II MHC-peptide complexes for presentation to T cells. Methodology/Principal Findings In this study we extend these findings to human DCs and distinguish between different subsets of DCs based on their ability to preserve internalized antigen. Whereas DCs derived in vitro from CD34+ hematopoietic progenitor cells or isolated from peripheral blood of healthy donors are protease poor, DCs derived in vitro from monocytes (MDDCs) are more similar to macrophages (MΦs) in protease content. Unlike other DCs, MDDCs also fail to reduce their intralysosomal pH in response to maturation stimuli. Indeed, functional characterization of lysosomal proteolysis indicates that MDDCs are comparable to MΦs in the rapid degradation of antigen while other human DC subtypes are attenuated in this capacity. Conclusions/Significance Human DCs are comparable to murine DCs in exhibiting a markedly reduced level of lysosomal proteolysis. However, as an important exception to this, human MDDCs stand apart from all other DCs by a heightened capacity for proteolysis that resembles that of MΦs. Thus, caution should be exercised when using human MDDCs as a model for DC function and cell biology. PMID:20689855

  14. Fibroblast growth factor 16 and 18 are expressed in human cardiovascular tissues and induce on endothelial cells migration but not proliferation

    SciTech Connect

    Antoine, M.; Wirz, W.; Tag, C.G.; Gressner, A.M.; Wycislo, M.; Mueller, R.; Kiefer, P. . E-mail: pkiefer@ukaachen.de

    2006-07-21

    Endothelial cells line the blood vessel and precursor endothelial cells appear to have a pivotal effect on the organ formation of the heart, the embryonic development of the kidney, and the liver. Several growth factors including the fibroblast growth factors (FGF) seem to be involved in these processes. Ligands such as basic FGF produced and secreted by endothelial cells may also coordinate cellular migration, differentiation, and proliferation under pathological conditions including wound healing, tumorgenesis, and fibrogenesis in the adult. Recently we demonstrated the expression of two secreted FGFs, FGF16, and FGF18, in HUVEC and in rat aortic tissue. In the present report, we confirmed by RT-PCR analysis that FGF18 is wildly expressed in the cardiovascular tissue, while FGF16 showed a more restricted expression pattern. HUVEC clearly demonstrated chemotaxis towards FGF16 and FGF18. Both FGFs also enhanced cell migration in response to mechanical damage. However, recombinant FGF16 and FGF18 failed to induce endothelial cell proliferation or sprouting in a three-dimensional in vitro angiogenesis assay. Fgf18 expression was earlier reported in the liver, and we detected FGF18 expression in liver vascular and liver sinusoidal endothelial cells (LSECs), but not in hepatic parenchymal cells. Recombinant FGF18 stimulated DNA synthesis in primary hepatocytes, suggesting, that endothelial FGF18 might have a paracrine function in promoting growth of the parenchymal tissue. Interestingly, FGF2, which is mitogenic on endothelial cells and hepatocytes stimulates a sustained MAPK activation in both cell types, while FGF18 causes a short transient activation of the MAPK pathway in endothelial cells but a sustained activation in hepatocytes. Therefore, the difference in the time course of MAPK activation by the different FGFs appears to be the cause for the different cellular responses.

  15. Canarypox Virus-Induced Maturation of Dendritic Cells Is Mediated by Apoptotic Cell Death and Tumor Necrosis Factor Alpha Secretion

    PubMed Central

    Ignatius, Ralf; Marovich, Mary; Mehlhop, Erin; Villamide, Loreley; Mahnke, Karsten; Cox, William I.; Isdell, Frank; Frankel, Sarah S.; Mascola, John R.; Steinman, Ralph M.; Pope, Melissa

    2000-01-01

    Recombinant avipox viruses are being widely evaluated as vaccines. To address how these viruses, which replicate poorly in mammalian cells, might be immunogenic, we studied how canarypox virus (ALVAC) interacts with primate antigen-presenting dendritic cells (DCs). When human and rhesus macaque monocyte-derived DCs were exposed to recombinant ALVAC, immature DCs were most susceptible to infection. However, many of the infected cells underwent apoptotic cell death, and dying infected cells were engulfed by uninfected DCs. Furthermore, a subset of DCs matured in the ALVAC-exposed DC cultures. DC maturation coincided with tumor necrosis factor alpha (TNF-α) secretion and was significantly blocked in the presence of anti-TNF-α antibodies. Interestingly, inhibition of apoptosis with a caspase 3 inhibitor also reduced some of the maturation induced by exposure to ALVAC. This indicates that both TNF-α and the presence of primarily apoptotic cells contributed to DC maturation. Therefore, infection of immature primate DCs with ALVAC results in apoptotic death of infected cells, which can be internalized by noninfected DCs driving DC maturation in the presence of the TNF-α secreted concomitantly by exposed cells. This suggests an important mechanism that may influence the immunogenicity of avipox virus vectors. PMID:11070033

  16. Effect of cell-derived growth factors and cytokines on the clonal outgrowth of EBV-infected B cells and established lymphoblastoid cell lines.

    PubMed

    Ifversen, P; Zhang, X M; Ohlin, M; Zeuthen, J; Borrebaeck, C A

    1993-07-01

    Epstein-Barr virus (EBV) is a potent inducer of polyclonal B lymphocyte proliferation and is widely used as a tool for the establishment of B cell lines producing human monoclonal antibodies. However, because of low transformability, low clonability, and the inherent instability of EBV-infected B cells, valuable antibody-producing B cells are often lost during this procedure. We have here examined various cell-derived cytokines for their ability to enhance both the cellular outgrowth of newly infected B cells and the clonability of infected B cells and lymphoblastoid cell lines. Our results show that the murine thymoma cell line EL-4 is superior to peripheral blood mononuclear cells in both cellular outgrowth and cloning experiments, whereas monocyte-derived factors and monocyte cell lines were less capable than peripheral blood mononuclear cells in enhancing cellular outgrowth and cloning. Furthermore, the human T cell hybridoma cell line MP6 that secretes a B cell growth and differentiation factor, recently identified as an isoform of thioredoxin, is also capable of stimulating EBV-infected B cells and lymphoblastoid cell lines. Co-cultivation of EBV-infected B cells with MP6 cells significantly enhanced the cloning efficiency at the 1 cell/well level. The present results also suggest that one potential role of the MP6-derived thioredoxin could be the up regulation of IL-6 receptor expression in EBV-infected B cells. PMID:8395232

  17. Krüppel-like Factor 4 modulates interleukin-6 release in human dendritic cells after in vitro stimulation with Aspergillus fumigatus and Candida albicans.

    PubMed

    Czakai, Kristin; Leonhardt, Ines; Dix, Andreas; Bonin, Michael; Linde, Joerg; Einsele, Hermann; Kurzai, Oliver; Loeffler, Jürgen

    2016-01-01

    Invasive fungal infections are associated with high mortality rates and are mostly caused by the opportunistic fungi Aspergillus fumigatus and Candida albicans. Immune responses against these fungi are still not fully understood. Dendritic cells (DCs) are crucial players in initiating innate and adaptive immune responses against fungal infections. The immunomodulatory effects of fungi were compared to the bacterial stimulus LPS to determine key players in the immune response to fungal infections. A genome wide study of the gene regulation of human monocyte-derived dendritic cells (DCs) confronted with A. fumigatus, C. albicans or LPS was performed and Krüppel-like factor 4 (KLF4) was identified as the only transcription factor that was down-regulated in DCs by both fungi but induced by stimulation with LPS. Downstream analysis demonstrated the influence of KLF4 on the interleukine-6 expression in human DCs. Furthermore, KLF4 regulation was shown to be dependent on pattern recognition receptor ligation. Therefore KLF4 was identified as a controlling element in the IL-6 immune response with a unique expression pattern comparing fungal and LPS stimulation. PMID:27346433

  18. Krüppel-like Factor 4 modulates interleukin-6 release in human dendritic cells after in vitro stimulation with Aspergillus fumigatus and Candida albicans

    PubMed Central

    Czakai, Kristin; Leonhardt, Ines; Dix, Andreas; Bonin, Michael; Linde, Joerg; Einsele, Hermann; Kurzai, Oliver; Loeffler, Jürgen

    2016-01-01

    Invasive fungal infections are associated with high mortality rates and are mostly caused by the opportunistic fungi Aspergillus fumigatus and Candida albicans. Immune responses against these fungi are still not fully understood. Dendritic cells (DCs) are crucial players in initiating innate and adaptive immune responses against fungal infections. The immunomodulatory effects of fungi were compared to the bacterial stimulus LPS to determine key players in the immune response to fungal infections. A genome wide study of the gene regulation of human monocyte-derived dendritic cells (DCs) confronted with A. fumigatus, C. albicans or LPS was performed and Krüppel-like factor 4 (KLF4) was identified as the only transcription factor that was down-regulated in DCs by both fungi but induced by stimulation with LPS. Downstream analysis demonstrated the influence of KLF4 on the interleukine-6 expression in human DCs. Furthermore, KLF4 regulation was shown to be dependent on pattern recognition receptor ligation. Therefore KLF4 was identified as a controlling element in the IL-6 immune response with a unique expression pattern comparing fungal and LPS stimulation. PMID:27346433

  19. Novel aspects of blood coagulation factor XIII. I. Structure, distribution, activation, and function

    SciTech Connect

    Muszbek, L.; Adany, R.; Mikkola, H.

    1996-10-01

    Blood coagulation factor XIII (FXIII) is a protransglutaminase that becomes activated by the concerted action of thrombin and Ca{sup 2+} in the final stage of the clotting cascade. In addition to plasma, FXIII also occurs in platelets, monocytes, and monocyte-derived macrophages. While the plasma factor is a heterotetramer consisting of paired A and B subunits (A{sub 2}B{sub 2}), its cellular counterpart lacks the B subunits and is a homodimer of potentially active A subunits (A{sub 2}). The gene coding for the A and B subunits has been localized to chromosomes 6p24-25 and 1q31-32.1, respectively. The genomic as well as the primary protein structure of both subunits has been established. Plasma FXIII circulates in association with its substrate precursor, fibrinogen. Fibrin(ogen) has an important regulatory role in the activation of plasma FXIII, for instance the proteolytic removal of activation peptide by thrombin, the dissociation of subunits A and B, and the exposure of the originally buried active site on the free A subunits. The end result of this process is the formation of an active transglutaminase, which crosslinks peptide chains through {epsilon}({gamma}-glutamyl)lysyl isopeptide bonds. The protein substrates of activated FXIII include components of the clotting-fibrinolytic system, adhesive and contractile proteins. The main physiological function of plasma FXIII is to cross-link fibrin and protect it from the fibrinolytic enzyme plasmin. The latter effect is achieved mainly by covalently linking {alpha}{sub 2} antiplasmin, the most potent physiological inhibitor of plasmin, to fibrin. Plasma FXIII seems to be involved in wound healing and tissue repair, and it is essential to maintaining pregnancy. Cellular FXIII, if exposed to the surface of the cells, might support or perhaps take over the hemostatic functions of plasma FXIII; however, its intracellular role has remained mostly unexplored. 328 refs., 4 figs.

  20. Rapid breakdown of phosphatidylinositol 4-phosphate and phosphatidylinositol 4,5-bisphosphate in rat hepatocytes stimulated by vasopressin and other Ca2+-mobilizing hormones.

    PubMed Central

    Creba, J A; Downes, C P; Hawkins, P T; Brewster, G; Michell, R H; Kirk, C J

    1983-01-01

    Rat hepatocytes rapidly incorporate [32P]Pi into phosphatidylinositol 4-phosphate (PtdIns4P) and phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2]; their monoester phosphate groups approach isotopic equilibrium with the cellular precursor pools within 1 h. Upon stimulation of these prelabelled cells with Ca2+-mobilizing stimuli (V1-vasopressin, angiotensin, alpha 1-adrenergic, ATP) there is a rapid fall in the labelling of PtdIns4P and PtdIns(4,5)P2. Pharmacological studies suggest that each of the four stimuli acts at a different population of receptors. Insulin, glucagon and prolactin do not provoke disappearance of labelled PtdIns4P and PtdIns(4,5)P2. The labelling of PtdIns4P and PtdIns(4,5)P2 in cells stimulated with vasopressin or angiotensin initially declines at a rate of 0.5-1.0% per s, reaches a minimum after 1-2 min and then returns towards the initial value. The dose-response curves for the vasopressin- and angiotensin-stimulated responses lie close to the respective receptor occupation curves, rather than at the lower hormone concentrations needed to evoke activation of glycogen phosphorylase. Disappearance of labelled PtdIns4P and PtdIns(4,5)P2 is not observed when cells are incubated with the ionophore A23187. The hormone-stimulated polyphosphoinositide disappearance is reduced, but not abolished, in Ca2+-depleted cells. These hormonal effects are not modified by 8-bromo cyclic GMP, cycloheximide or delta-hexachlorocyclohexane. The absolute rate of polyphosphoinositide breakdown in stimulated cells is similar to the rate previously reported for the disappearance of phosphatidylinositol [Kirk, Michell & Hems (1981) Biochem. J. 194, 155-165]. It seems likely that these changes in polyphosphoinositide labelling are caused by hormonal activation of the breakdown of PtdIns(4,5)P2 (and may be also PtdIns4P) by the action of a polyphosphoinositide phosphodiesterase. We therefore suggest that the initial response to hormones is breakdown of PtdIns(4,5)P2 (and PtdIns4P?), and that the simultaneous disappearance of phosphatidylinositol might be a result of its consumption for the continuing synthesis of polyphosphoinositides. PMID:6309153

  1. Monocyte tissue factor-dependent activation of coagulation in hypercholesterolemic mice and monkeys is inhibited by simvastatin.

    PubMed

    Owens, A Phillip; Passam, Freda H; Antoniak, Silvio; Marshall, Stephanie M; McDaniel, Allison L; Rudel, Lawrence; Williams, Julie C; Hubbard, Brian K; Dutton, Julie-Ann; Wang, Jianguo; Tobias, Peter S; Curtiss, Linda K; Daugherty, Alan; Kirchhofer, Daniel; Luyendyk, James P; Moriarty, Patrick M; Nagarajan, Shanmugam; Furie, Barbara C; Furie, Bruce; Johns, Douglas G; Temel, Ryan E; Mackman, Nigel

    2012-02-01

    Hypercholesterolemia is a major risk factor for atherosclerosis. It also is associated with platelet hyperactivity, which increases morbidity and mortality from cardiovascular disease. However, the mechanisms by which hypercholesterolemia produces a procoagulant state remain undefined. Atherosclerosis is associated with accumulation of oxidized lipoproteins within atherosclerotic lesions. Small quantities of oxidized lipoproteins are also present in the circulation of patients with coronary artery disease. We therefore hypothesized that hypercholesterolemia leads to elevated levels of oxidized LDL (oxLDL) in plasma and that this induces expression of the procoagulant protein tissue factor (TF) in monocytes. In support of this hypothesis, we report here that oxLDL induced TF expression in human monocytic cells and monocytes. In addition, patients with familial hypercholesterolemia had elevated levels of plasma microparticle (MP) TF activity. Furthermore, a high-fat diet induced a time-dependent increase in plasma MP TF activity and activation of coagulation in both LDL receptor-deficient mice and African green monkeys. Genetic deficiency of TF in bone marrow cells reduced coagulation in hypercholesterolemic mice, consistent with a major role for monocyte-derived TF in the activation of coagulation. Similarly, a deficiency of either TLR4 or TLR6 reduced levels of MP TF activity. Simvastatin treatment of hypercholesterolemic mice and monkeys reduced oxLDL, monocyte TF expression, MP TF activity, activation of coagulation, and inflammation, without affecting total cholesterol levels. Our results suggest that the prothrombotic state associated with hypercholesterolemia is caused by oxLDL-mediated induction of TF expression in monocytes via engagement of a TLR4/TLR6 complex. PMID:22214850

  2. Reduced Simian Immunodeficiency Virus Replication in Macrophages of Sooty Mangabeys Is Associated with Increased Expression of Host Restriction Factors

    PubMed Central

    Mir, Kiran D.; Mavigner, Maud; Wang, Charlene; Paiardini, Mirko; Sodora, Donald L.; Chahroudi, Ann M.; Bosinger, Steven E.

    2015-01-01

    ABSTRACT Macrophages are target cells of HIV/SIV infection that may play a role in AIDS pathogenesis and contribute to the long-lived reservoir of latently infected cells during antiretroviral therapy (ART). In previous work, we and others have shown that during pathogenic SIV infection of rhesus macaques (RMs), rapid disease progression is associated with high levels of in vivo macrophage infection. In contrast, during nonpathogenic SIV infection of sooty mangabeys (SMs), neither spontaneous nor experimental CD4+ T cell depletion results in substantial levels of in vivo macrophage infection. To test the hypothesis that SM macrophages are intrinsically more resistant to SIV infection than RM macrophages, we undertook an in vitro comparative assessment of monocyte-derived macrophages (MDMs) from both nonhuman primate species. Using the primary isolate SIVM949, which replicates well in lymphocytes from both RMs and SMs, we found that infection of RM macrophages resulted in persistent SIV-RNA production while SIV-RNA levels in SM macrophage cultures decreased 10- to 100-fold over a similar temporal course of in vitro infection. To explore potential mechanisms responsible for the lower levels of SIV replication and/or production in macrophages from SMs we comparatively assessed, in the two studied species, the expression of the SIV coreceptor as well as the expression of a number of host restriction factors. While previous studies showed that SM monocytes express lower levels of CCR5 (but not CD4) than RM monocytes, the level of CCR5 expression in MDMs was similar in the two species. Interestingly, we found that SM macrophages exhibited a significantly greater increase in the expression of tetherin (P = 0.003) and TRIM22 (P = 0.0006) in response to alpha interferon stimulation and increased expression of multiple host restriction factors in response to lipopolysaccharide stimulation and exposure to SIV. Overall, these findings confirm, in an in vitro infection system

  3. Thalidomide treatment reduces tumor necrosis factor alpha production and enhances weight gain in patients with pulmonary tuberculosis.

    PubMed Central

    Tramontana, J. M.; Utaipat, U.; Molloy, A.; Akarasewi, P.; Burroughs, M.; Makonkawkeyoon, S.; Johnson, B.; Klausner, J. D.; Rom, W.; Kaplan, G.

    1995-01-01

    BACKGROUND: The monocyte-derived cytokine, tumor necrosis factor alpha (TNF alpha), is essential for host immunity, but overproduction of this cytokine may have serious pathologic consequences. Excess TNF alpha produced in pulmonary tuberculosis may cause fevers, weakness, night sweats, necrosis, and progressive weight loss. Thalidomide (alpha-N-phthalimidoglutarimide) has recently been shown to suppress TNF alpha production by human monocytes in vitro and to reduce serum TNF alpha in leprosy patients. We have therefore conducted a two-part placebo-controlled pilot study of thalidomide in patients with active tuberculosis to determine its effects on clinical response, immune reactivity, TNF alpha levels, and weight. MATERIALS AND METHODS: 30 male patients with active tuberculosis, either human immunodeficiency virus type 1 positive (HIV-1+) or HIV-1-, received thalidomide or placebo for single or multiple 14 day cycles. Toxicity of the study drug, delayed type hypersensitivity (DTH), cytokine production, and weight gain were evaluated. RESULTS: Thalidomide treatment was well tolerated, without serious adverse events. The drug did not adversely affect the DTH response to purified protein derivative (PPD), total leukocyte, or differential cell counts. TNF alpha production was significantly reduced during thalidomide treatment while interferon-gamma (IFN gamma) production was enhanced. Daily administration of thalidomide resulted in a significant enhancement of weight gain. CONCLUSIONS: The results indicate that thalidomide is well tolerated by patients receiving anti-tuberculosis therapy. Thalidomide treatment reduces TNF alpha production both in vivo and in vitro and is associated with an accelerated weight gain during the study period. PMID:8521296

  4. Induction of TRAIL- and TNF-α-dependent Apoptosis in Human Monocyte-derived Dendritic Cells by Microfilariae of Brugia Malayi1

    PubMed Central

    Semnani, Roshanak Tolouei; Venugopal, Priyanka Goel; Mahapatra, Lily; Skinner, Jason; Meylan, Francoise; Chien, Daniel; Dorward, David; Chaussabel, Damien; Siegel, Richard M.; Nutman, Thomas B.

    2013-01-01

    Dysregulation of professional APC has been postulated as a major mechanism underlying Ag-specific T cell hyporesponsiveness in patients with patent filarial infection. To address the nature of this dysregulation, dendritic cells (DC) and macrophages (MΦ) generated from elutriated monocytes were exposed to live microfilariae (mf), the parasite stage that circulates in blood and is responsible for most immune dysregulation in filarial infections. DC exposed to mf for 24–96 h showed a marked increase in cell death and caspase-positive cells compared with unexposed DC, while mf exposure did not induce apoptosis in MΦ. Interestingly, 48 h exposure of DC to mf induced mRNA expression of the pro-apoptotic gene TRAIL and both mRNA and protein expression of TNF-α. mAb to TRAIL-R2, TNF-R1, or TNF-α partially reversed mf-induced cell death in DC, as did knocking down the receptor for TRAIL-R2 using small interfering RNA. Mf also induced gene expression of BH3-interacting domain death agonist (Bid) and protein expression of cytochrome c in DC; mf-induced cleavage of Bid could be shown to induce release of cytochrome c, leading to activation of caspase 9. Our data suggest that mf induce DC apoptosis in a TRAIL- and TNF-α-dependent fashion. PMID:18981128

  5. Development of ostrich thrombocytes and monocyte-derived macrophages in culture and the control of Toxoplasma gondii reproduction after macrophage activation.

    PubMed

    Miranda, Farlen J B; Damasceno-Sá, João Cláudio; DaMatta, Renato A

    2016-01-01

    Raising ostriches became an important economic activity after their products became commodities. The health of farm animals is of paramount importance, so assessing basic immunological responses is necessary to better understand health problems. We developed a method to obtain ostrich thrombocytes and macrophages. The thrombocytes died by apoptosis after 48 h in culture, and the macrophages expanded in size and increased the number of acidic compartments. Macrophages were activated by chicken interferon-γ, producing high levels of nitric oxide. Toxoplasma gondii was able to infect these macrophages, and activation controlled parasitic reproduction. T. gondii, however, persisted in these cells, and infection reduced the production of nitric oxide. These results are important for the future assessment of the basic cellular and immunobiology of ostriches and demonstrate T. gondii suppression of nitric oxide production. PMID:26794839

  6. Ex vivo recovery and activation of dysfunctional, anergic, monocyte-derived dendritic cells from patients with operable breast cancer: critical role of IFN-alpha

    PubMed Central

    Satthaporn, Sukchai; Aloysius, Mark M; Robins, Richard A; Verma, Chandan; Chuthapisith, Suebwong; Mckechnie, Alasdair J; El-Sheemy, Mohamad; Vassanasiri, Wichai; Valerio, David; Clark, David; Jibril, Jibril A; Eremin, Oleg

    2008-01-01

    Background Dendritic cells (DCs) play a crucial role in initiating effective cell-mediated immune responses, but are dysfunctional and anergic in breast cancer. Reversal of this dysfunction and establishment of optimal DC function is a key prerequisite for the induction of effective anti-cancer immune responses. Results Peripheral blood DCs (PBDCs) and lymph node DCs (LNDCs) generated in vitro from adherent cultures of peripheral blood monocytes (PBMs) and lymph node monocytes (LNMs), respectively, using the 4 cytokine conditioned medium (CCM) (GM-CSF+IL-4+TNF-α+IFN-α) or 3 CCM (GM-CSF+IL-4+TNF-α) demonstrated a significantly higher degree of recovery and functional capacity in a mixed lymphocyte DC reaction (MLDCR, p < 0.001), expressed significantly higher levels of HLA-DR, CD86, compared with 2 CCM (GM-CSF+IL-4) or medium alone generated DCs from PBMs and LNMs (p < 0.001). The PBDCs generated with 3 CCM or 4 CCM showed a significantly (p < 0.001) enhanced macropinocytotic capability (dextran particles) and induced increased production and secretion of interleukin-12p40 (IL-12p40) in vitro (p < 0.001), compared with PBDCs generated from monocytes using 2 CCM or medium alone. Lipopolysaccharide (LPS) stimulation of PBDCs generated with 4 CCM demonstrated enhanced secretion of IL-6 but not IL-12p70, compared with control DCs unstimulated with LPS (p < 0.001). Conclusion Dysfunctional and anergic PBDCs and LNDCs from patients with operable breast cancer can be optimally reversed by ex vivo culturing of precursor adherent monocytes using a 4 CCM containing IFN-α. Maximal immunophenotypic recovery and functional reactivation of DCs is seen in the presence of IFN-α. However, 4 CCM containing IFN-α generated-PBDCs, do not produce and secrete IL-12p70 in vitro. PMID:18588665

  7. In vitro T-cell activation of monocyte-derived macrophages by soluble messengers or cell-to-cell contact in bovine tuberculosis

    PubMed Central

    Liébana, E; Aranaz, A; Welsh, M; Neill, S D; Pollock, J M

    2000-01-01

    The macrophage plays a dual role in tuberculosis, promoting not only protection against mycobacteria, but also survival of the pathogen. Macrophages inhibit multiplication of mycobacteria but also act in concert with lymphocytes through presentation of antigens to T cells. Studies in animal and human infections have suggested a correlation of in vitro growth rates of mycobacteria with in vivo virulence, using uracil uptake to assess mycobacterial metabolism. This study found that blood-derived, non-activated bovine macrophages were capable of controlling Mycobacterium bovis bacillus Calmette–Guérin growth for up to 96 hr, but were permissive to intracellular growth of virulent M. bovis. The present investigation compared the in vitro modulation of these macrophage activities by cytokine-rich T-cell supernatants or cell-to-cell contact. On the one hand, treatment of cultured monocytes with mitogen-produced T-cell supernatants promoted morphological changes suggestive of an activation status, enhanced the antigen presentation capabilities of monocytes and up-regulated major histocompatibility complex class II expression. However, this activation was not associated with enhanced anti-M. bovis activity. On the other hand, incubation of infected monocytes with T-cell populations resulted in proportionally increased inhibition of M. bovis uracil uptake. This inhibition was also seen using cells from uninfected animals and indicated the necessity for cell-to-cell contact to promote antimycobacterial capability. PMID:10886395

  8. HIV-1-infected monocyte-derived dendritic cells do not undergo maturation but can elicit IL-10 production and T cell regulation

    NASA Astrophysics Data System (ADS)

    Granelli-Piperno, Angela; Golebiowska, Angelika; Trumpfheller, Christine; Siegal, Frederick P.; Steinman, Ralph M.

    2004-05-01

    Dendritic cells (DCs) undergo maturation during virus infection and thereby become potent stimulators of cell-mediated immunity. HIV-1 replicates in immature DCs, but we now find that infection is not accompanied by many components of maturation in either infected cells or uninfected bystanders. The infected cultures do not develop potent stimulating activity for the mixed leukocyte reaction (MLR), and the DCs producing HIV-1 gag p24 do not express CD83 and DC-lysosome-associated membrane protein maturation markers. If different maturation stimuli are applied to DCs infected with HIV-1, the infected cells selectively fail to mature. When DCs from HIV-1-infected patients are infected and cultured with autologous T cells, IL-10 was produced in 6 of 10 patients. These DC-T cell cocultures could suppress another immune response, the MLR. The regulation was partially IL-10-dependent and correlated in extent with the level of IL-10 produced. Suppressor cells only developed from infected patients, rather than healthy controls, and the DCs had to be exposed to live virus rather than HIV-1 gag peptides or protein. These results indicate that HIV-1-infected DCs have two previously unrecognized means to evade immune responses: maturation can be blocked reducing the efficacy of antigen presentation from infected cells, and T cell-dependent suppression can be induced.

  9. Comparative analysis of signature genes in porcine reproductive and respiratory syndrome virus (PRRSV)-infected porcine monocyte-derived dendritic cells at differential activation statuses

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Activation statuses of monocytic cells, e.g. monocytes, macrophages and dendritic cells (DCs), are critically important for antiviral immunity. In particular, some devastating viruses, including porcine reproductive and respiratory syndrome virus (PRRSV), are capable of directly infecting these cell...

  10. Maturation of monocyte derived dendritic cells with OK432 boosts IL-12p70 secretion and conveys strong T-cell responses

    PubMed Central

    2011-01-01

    Background Design of tumour specific immunotherapies using the patients' own dendritic cells (DC) is a fast advancing scientific field. The functional qualities of the DC generated in vitro are critical, and today's gold standard for maturation is a cytokine cocktail consisting of IL-1β, IL-6, TNF-α and PGE2 generating cells lacking IL-12p70 production. OK432 is an immunotherapeutic agent derived from killed Streptococcus pyogenes that has been used clinically to treat malignant and benign neoplasms for decades. Methods In this study, we analysed the effects of OK432 on DC maturation, DC migration, cytokine and chemokine secretion as well as T-cell stimulatory capacity, and compared it to the cytokine cocktail alone and combinations of OK432 with the cytokine cocktail. Results OK432 induced a marked up-regulation of CD40 on the cell surface as well as a strong inflammatory response from the DC with significantly more secretion of 19 different cytokines and chemokines compared to the cytokine cocktail. Interestingly, secretion of IL-15 and IL-12p70 was detected at high concentrations after maturation of DC with OK432. However, the OK432 treated DC did not migrate as well as DC treated with cytokine cocktail in a transwell migration assay. During allogeneic T-cell stimulation OK432 treated DC induced proliferation of over 50 percent of CD4 and 30 percent of CD8 T-cells for more than two cell divisions, whereas cytokine cocktail treated DC induced proliferation of 12 and 11 percent of CD4 and CD8 T-cells, respectively. Conclusions The clinically approved compound OK432 has interesting properties that warrants its use in DC immunotherapy and should be considered as a potential immunomodulating agent in cancer immunotherapy. PMID:21208424

  11. Changes in the proteomic profile during the differential polarization status of the human monocyte-derived macrophage THP-1 cell line.

    PubMed

    Zhang, Fan; Liu, Hao; Jiang, Guanmin; Wang, Hongsheng; Wang, Xianfeng; Wang, Hao; Fang, Rui; Cai, Shaohui; Du, Jun

    2015-02-01

    Macrophages are heterogeneous and plastic populations that are an essential component of inflammation and host defense. To understand how macrophages respond to cytokine signals, we used 2DE to identify protein profiles in macrophages stimulated with interleukin 4 (M2) and those stimulated with lipopolysaccharide and interferon γ (M1). In total, 32 differentially expressed proteins in THP-1 cells were identified by MALDI-TOF MS/MS analysis. The different proteins were mainly involved in cellular structure, protein metabolism, stress response, oxidative response, and nitric oxide production during macrophage polarization. In particular, proteins playing important roles in production of nitric oxide (NO) were downregulated in M2 macrophages. Many antioxidant and heat shock proteins, which are related to oxidative response, were upregulated in M2 macrophages. More importantly, a remarkable decrease in intracellular ROS and NO production were detected in M2 macrophages. Our results provide a proteomic profile of differentially polarized macrophages and validate the function of the identified proteins, which may indicate possible mechanism of macrophage polarization process. PMID:25411139

  12. The effect of particle agglomeration on the formation of a surface-connected compartment induced by hydroxyapatite nanoparticles in human monocyte-derived macrophages☆

    PubMed Central

    Müller, Karin H.; Motskin, Michael; Philpott, Alistair J.; Routh, Alexander F.; Shanahan, Catherine M.; Duer, Melinda J.; Skepper, Jeremy N.

    2014-01-01

    Agglomeration dramatically affects many aspects of nanoparticle–cell interactions. Here we show that hydroxyapatite nanoparticles formed large agglomerates in biological medium resulting in extensive particle uptake and dose-dependent cytotoxicity in human macrophages. Particle citration and/or the addition of the dispersant Darvan 7 dramatically reduced mean agglomerate sizes, the amount of particle uptake and concomitantly cytotoxicity. More surprisingly, agglomeration governed the mode of particle uptake. Agglomerates were sequestered within an extensive, interconnected membrane labyrinth open to the extracellular space. In spite of not being truly intracellular, imaging studies suggest particle degradation occurred within this surface-connected compartment (SCC). Agglomerate dispersion prevented the SCC from forming, but did not completely inhibit nanoparticle uptake by other mechanisms. The results of this study could be relevant to understanding particle–cell interactions during developmental mineral deposition, in ectopic calcification in disease, and during application of hydroxyapatite nanoparticle vectors in biomedicine. PMID:24183166

  13. Sarcoplasmic reticulum Ca2+ ATPase 2 (SERCA2) reduces the migratory capacity of CCL21-treated monocyte-derived dendritic cells

    PubMed Central

    Hong, Cheol Yi; Lee, Hyun-Ju; Choi, Nu-Ri; Jung, Sung-Hoon; Vo, Manh-Cuong; Hoang, My Dung; Kim, Hyeoung-Joon; Lee, Je-Jung

    2016-01-01

    The migration of dendritic cells (DCs) to secondary lymphoid organs depends on chemoattraction through the interaction of the chemokine receptors with chemokines. However, the mechanism of how lymphoid chemokines attract DCs to lymphoid organs remains unclear. Here, we demonstrate the mechanism of DC migration in response to the lymphoid chemokine CCL21. CCL21-mediated DC migration is controlled by the regulation of sarcoplasmic reticulum Ca2+ ATPase 2 (SERCA2) expression rather than through the activation of mitogen-activated protein kinases CCL21-exposed mature DCs (mDCs) exhibited decreased SERCA2 expression but not decreased phospholamban (PLB) or Hax-1 expression, which are known to be SERCA2-interacting proteins. In addition, CCL21 did not affect the mRNA levels of SERCA2 or its interacting protein Hax-1. Interestingly, SERCA2 expression was inversely related to DC migration in response to chemokine stimulation. The migratory capacity of CCL21-treated mDCs was decreased by the phospholipase C inhibitor U73122 and by the protein kinase C inhibitor BAPTA-AM. The migratory capacities of mDCs were increased in response to SERCA2 siRNA expression but were decreased by SERCA2 overexpression. In addition, DCs treated with a SERCA2-specific inhibitor (cyclopiazonic acid) had significantly increased migratory capacities as mDCs regardless of SERCA2 expression. Moreover, SERCA2 expression was dependent on DC maturation induced by cytokines or Toll-like receptor agonists. Therefore, the migratory capacities differed in differentially matured DCs. Taken together, these results suggest that SERCA2 contributes to the migration of CCL21-activated DCs as an important feature of the adaptive immune response and provide novel insights regarding the role of SERCA2 in DC functions. PMID:27538371

  14. HIV-1 Tat Protein Induces PD-L1 (B7-H1) Expression on Dendritic Cells through Tumor Necrosis Factor Alpha- and Toll-Like Receptor 4-Mediated Mechanisms

    PubMed Central

    Planès, Rémi; BenMohamed, Lbachir; Leghmari, Kaoutar; Delobel, Pierre; Izopet, Jacques

    2014-01-01

    ABSTRACT Chronic human immunodeficiency virus type 1 (HIV-1) infection is associated with induction of T-cell coinhibitory pathways. However, the mechanisms by which HIV-1 induces upregulation of coinhibitory molecules remain to be fully elucidated. The aim of the present study was to determine whether and how HIV-1 Tat protein, an immunosuppressive viral factor, induces the PD-1/PD-L1 coinhibitory pathway on human dendritic cells (DCs). We found that treatment of DCs with whole HIV-1 Tat protein significantly upregulated the level of expression of PD-L1. This PD-L1 upregulation was observed in monocyte-derived dendritic cells (MoDCs) obtained from either uninfected or HIV-1-infected patients as well as in primary myeloid DCs from HIV-negative donors. In contrast, no effect on the expression of PD-L2 or PD-1 molecules was detected. The induction of PD-L1 on MoDCs by HIV-1 Tat (i) occurred in dose- and time-dependent manners, (ii) was mediated by the N-terminal 1–45 fragment of Tat, (iii) did not require direct cell-cell contact but appeared rather to be mediated by soluble factor(s), (iv) was abrogated following neutralization of tumor necrosis factor alpha (TNF-α) or blocking of Toll-like receptor 4 (TLR4), (v) was absent in TLR4-knockoout (KO) mice but could be restored following incubation with Tat-conditioned medium from wild-type DCs, (vi) impaired the capacity of MoDCs to functionally stimulate T cells, and (vii) was not reversed functionally following PD-1/PD-L1 pathway blockade, suggesting the implication of other Tat-mediated coinhibitory pathways. Our results demonstrate that HIV-1 Tat protein upregulates PD-L1 expression on MoDCs through TNF-α- and TLR4-mediated mechanisms, functionally compromising the ability of DCs to stimulate T cells. The findings offer a novel potential molecular target for the development of an anti-HIV-1 treatment. IMPORTANCE The objective of this study was to investigate the effect of human immunodeficiency virus type 1 (HIV

  15. Infection of peripheral blood mononuclear cells by herpes simplex and Epstein-Barr viruses. Differential induction of interleukin 6 and tumor necrosis factor-alpha.

    PubMed Central

    Gosselin, J; Flamand, L; D'Addario, M; Hiscott, J; Menezes, J

    1992-01-01

    Infection by herpesviruses can result in profound immunosuppressive or immunomodulatory effects. However, no significant information is available on the effect of such infections on the production of immunoregulatory cytokines. We studied the kinetics of production of two monocyte-derived cytokines, interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF alpha), induced by Epstein-Barr virus (EBV) and herpes simplex virus type 1 (HSV-1) in peripheral blood mononuclear cell cultures and in fractionated cell populations. We observed that, when compared to HSV-1, EBV is a stronger inducer of IL-6. In EBV-infected cultures, IL-6 protein was detected at day 1 postinfection and gradually increased with time. In contrast, lower amounts of IL-6 were detected 5 d postinfection in HSV-1-infected cultures. HSV-1-infected cultures secreted significant amounts of TNF alpha protein after 5 d of culture and reached a maximal level of production at day 7, whereas EBV inhibited TNF alpha production. In fractionated cell populations, monocytic cells were found to be the main source of IL-6 synthesis after EBV or HSV-1 infection. However, TNF alpha synthesis in HSV-1-infected cultures was from both B and monocytic cells. By using the polymerase chain reaction technique we show that, after infection by these two herpesviruses, differences in cytokine gene products are also observed at the transcriptional level. These observations demonstrate that EBV and HSV-1 exert differential effects on IL-6 and TNF alpha gene transcription and on the resulting protein secretion in human mononuclear blood cells. Images PMID:1318324

  16. Epithelial cells prime the immune response to an array of gut-derived commensals towards a tolerogenic phenotype through distinct actions of thymic stromal lymphopoietin and transforming growth factor

    PubMed Central

    Zeuthen, Louise Hjerrild; Fink, Lisbeth Nielsen; Frokiaer, Hanne

    2008-01-01

    Humans and other mammals coexist with a diverse array of microbes colonizing the intestine, termed the microflora. The relationship is symbiotic, with the microbes benefiting from a stable environment and nutrient supply, and the host gaining competitive exclusion of pathogens and continuously maintenance of the gut immune homeostasis. Here we report novel crosstalk mechanisms between the human enterocyte cell line, Caco2, and underlying human monocyte-derived DC in a transwell model where Gram-positive (G+) commensals prevent Toll-like receptor-4 (TLR4)-dependent Escherichia coli-induced semimaturation in a TLR2-dependent fashion. These findings add to our understanding of the hypo-responsiveness of the gut epithelium towards the microflora. Gut DC posses a more tolerogenic phenotype than conventional DC. Here we show that Caco2 spent medium (SM) induces tolerogenic DC with lower expression of maturation markers, interleukin (IL)-12p70, and tumour necrosis factor-α when matured with G+ and Gram-negative (G–) commensals, while IL-10 production is enhanced in DC upon encountering G+ commensals and reduced upon encountering G– bacteria. The Caco2 SM-induced tolerogenic phenotype is also seen in DC priming of naive T cells with elevated levels of transforming growth factor-β (TGF-β) and markedly reduced levels of bacteria-induced interferon-γ production. Caco2 cell production of IL-8, thymic stromal lymphopoietin (TSLP) and TGF-β increases upon microbial stimulation in a strain dependent manner. TSLP and TGF-β co-operate in inducing the tolerogenic DC phenotype but other mediators might be involved. PMID:17655740

  17. Evaluation of transduction efficiency in macrophage colony-stimulating factor differentiated human macrophages using HIV-1 based lentiviral vectors

    PubMed Central

    2011-01-01

    Background Monocyte-derived macrophages contribute to atherosclerotic plaque formation. Therefore, manipulating macrophage function could have significant therapeutic value. The objective of this study was to determine transduction efficiency of two HIV-based lentiviral vector configurations as delivery systems for the transduction of primary human blood monocyte-derived macrophages. Results Human blood monocytes were transduced using two VSV-G pseudotyped HIV-1 based lentiviral vectors containing EGFP expression driven by either native HIV-LTR (VRX494) or EF1α promoters (VRX1090). Lentiviral vectors were added to cultured macrophages at different times and multiplicities of infection (MOI). Transduction efficiency was assessed using fluorescence microscopy and flow cytometry. Macrophages transduced between 2 and 120 hours after culturing showed the highest transduction efficiency at 2-hours transduction time. Subsequently, cells were transduced 2 hours after culturing at various vector concentrations (MOIs of 5, 10, 25 and 50) to determine the amount of lentiviral vector particles required to maximally transduce human monocyte-derived macrophages. On day 7, all transduced cultures showed EGFP-positive cells by microscopy. Flow cytometric analysis showed with all MOIs a peak shift corresponding to the presence of EGFP-positive cells. For VRX494, transduction efficiency was maximal at an MOI of 25 to 50 and ranged between 58 and 67%. For VRX1090, transduction efficiency was maximal at an MOI of 10 and ranged between 80 and 90%. Thus, transductions performed with VRX1090 showed a higher number of EGFP-positive cells than VRX494. Conclusions This report shows that VSV-G pseudotyped HIV-based lentiviral vectors can efficiently transduce human blood monocyte-derived macrophages early during differentiation using low particle numbers that do not interfere with differentiation of monocytes into macrophages. PMID:21281514

  18. Per a 10 protease activity modulates CD40 expression on dendritic cell surface by nuclear factor-kappaB pathway

    PubMed Central

    Goel, C; Kalra, N; Dwarakanath, B S; Gaur, S N; Arora, N

    2015-01-01

    Serine protease activity of Per a 10 from Periplaneta americana modulates dendritic cell (DC) functions by a mechanism(s) that remains unclear. In the present study, Per a 10 protease activity on CD40 expression and downstream signalling was evaluated in DCs. Monocyte-derived DCs from cockroach-allergic patients were treated with proteolytically active/heat-inactivated Per a 10. Stimulation with active Per a 10 demonstrated low CD40 expression on DCs surface (P < 0·05), while enhanced soluble CD40 level in the culture supernatant (P < 0·05) compared to the heat-inactivated Per a 10, suggesting cleavage of CD40. Per a 10 activity reduced the interleukin (IL)-12 and interferon (IFN)-γ secretion by DCs (P < 0·05) compared to heat-inactivated Per a 10, indicating that low CD40 expression is associated with low levels of IL-12 secretion. Active Per a 10 stimulation caused low nuclear factor-kappa B (NF-κB) activation in DCs compared to heat-inactivated Per a 10. Inhibition of the NF-κB pathway suppressed the CD40 expression and IL-12 secretion by DCs, further indicating that NF-κB is required for CD40 up-regulation. CD40 expression activated the tumour necrosis factor (TNF) receptor-associated factor 6 (TRAF6), thereby suggesting its involvement in NF-κB activation. Protease activity of Per a 10 induced p38 mitogen-activated protein kinase (MAPK) activation that showed no significant effect on CD40 expression by DCs. However, inhibiting p38 MAPK or NF-κB suppressed the secretion of IL-12, IFN-γ, IL-6 and TNF-α by DCs. Such DCs further reduced the secretion of IL-4, IL-6, IL-12 and TNF-α by CD4+ T cells. In conclusion, protease activity of Per a 10 reduces CD40 expression on DCs. CD40 down-regulation leads to low NF-κB levels, thereby modulating DC-mediated immune responses. PMID:25492061

  19. Factor XII (Hageman factor) deficiency

    MedlinePlus

    ... takes longer than normal to clot in a test tube. Factor XII deficiency is a rare inherited disorder. Symptoms There are usually no symptoms. Exams and Tests Factor XII deficiency is most often found when ...

  20. Quality factors

    SciTech Connect

    Kerr, G.D.

    1986-01-01

    The quality factor, Q, is a dimensionless modifier used in converting absorbed dose, expressed in rads (or grays), to dose equivalent, expressed in rems (or seiverts). The dose equivalent is used in radiation protection to account for the biological effectiveness of different kinds of radiation. The quality factor is related to both the linear energy transfer (LET) and relative biological effectiveness (RBE). The RBE's obtained from biological experiments depend in a complex way on the observed biological effect, the specific test organism, and the experimental conditions. Judgement is involved, therefore, in the choice of the quality factor. Questions regarding the adequacy of current Q values for neutrons were raised first in a 1980 statement by the National Council on Radiation Protection (NCRP) and later in a 1985 statement by the International Commission on Radiological Protection (ICRP). In 1980, the NCRP alerted the technical community to possible future increases between a factor of three and ten in the Q for neutrons, and in 1985, the ICRP suggested an increase by a factor of two in Q for neutrons. Both the ICRP and NRCP are now recommending essentially the same guidance with regard to Q for neutrons: an increase by a factor of two. The Q for neutrons is based on a large, albeit unfocused, body of experimental data. In spite of the lack of focus, the data supporting a change in the neutron quality factor are substantial. However, the proposed doubling of Q for neutrons is clouded by other issues regarding its application. 33 refs., 4 figs., 6 tabs.

  1. Rethinking Factors

    ERIC Educational Resources Information Center

    Feldman, Ziv

    2014-01-01

    This article describes an exciting exploration-based activity in which students develop an alternative definition of factor that can help them solve problems like the one presented above. Students work in groups to collect data, analyze the data to make conjectures, and then spend a significant amount of time debating and justifying their…

  2. Complex Interplay between HIV-1 Capsid and MX2-Independent Alpha Interferon-Induced Antiviral Factors

    PubMed Central

    Bulli, Lorenzo; Apolonia, Luis; Kutzner, Juliane; Pollpeter, Darja; Goujon, Caroline; Herold, Nikolas; Schwarz, Sarah-Marie; Giernat, Yannick; Keppler, Oliver T.

    2016-01-01

    ABSTRACT Type I interferons (IFNs), including IFN-α, upregulate an array of IFN-stimulated genes (ISGs) and potently suppress Human immunodeficiency virus type 1 (HIV-1) infectivity in CD4+ T cells, monocyte-derived macrophages, and dendritic cells. Recently, we and others identified ISG myxovirus resistance 2 (MX2) as an inhibitor of HIV-1 nuclear entry. However, additional antiviral blocks exist upstream of nuclear import, but the ISGs that suppress infection, e.g., prior to (or during) reverse transcription, remain to be defined. We show here that the HIV-1 CA mutations N74D and A105T, both of which allow escape from inhibition by MX2 and the truncated version of cleavage and polyadenylation specific factor 6 (CPSF6), as well as the cyclophilin A (CypA)-binding loop mutation P90A, all increase sensitivity to IFN-α-mediated inhibition. Using clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 technology, we demonstrate that the IFN-α hypersensitivity of these mutants in THP-1 cells is independent of MX2 or CPSF6. As expected, CypA depletion had no additional effect on the behavior of the P90A mutant but modestly increased the IFN-α sensitivity of wild-type virus. Interestingly, the infectivity of wild-type or P90A virus could be rescued from the MX2-independent IFN-α-induced blocks in THP-1 cells by treatment with cyclosporine (Cs) or its nonimmunosuppressive analogue SDZ-NIM811, indicating that Cs-sensitive host cell cyclophilins other than CypA contribute to the activity of IFN-α-induced blocks. We propose that cellular interactions with incoming HIV-1 capsids help shield the virus from recognition by antiviral effector mechanisms. Thus, the CA protein is a fulcrum for the dynamic interplay between cell-encoded functions that inhibit or promote HIV-1 infection. IMPORTANCE HIV-1 is the causative agent of AIDS. During acute HIV-1 infection, numerous proinflammatory cytokines are produced, including type I interferons (IFNs). IFNs can

  3. Measles Virus Induces Functional TRAIL Production by Human Dendritic Cells

    PubMed Central

    Vidalain, Pierre-Olivier; Azocar, Olga; Lamouille, Barbara; Astier, Anne; Rabourdin-Combe, Chantal; Servet-Delprat, Christine

    2000-01-01

    Measles virus infection induces a profound immunosuppression that can lead to serious secondary infections. Here we demonstrate that measles virus induces tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) mRNA and protein expression in human monocyte-derived dendritic cells. Moreover, measles virus-infected dendritic cells are shown to be cytotoxic via the TRAIL pathway. PMID:10590149

  4. Lactic Acid Bacteria Inducing a Weak Interleukin-12 and Tumor Necrosis Factor Alpha Response in Human Dendritic Cells Inhibit Strongly Stimulating Lactic Acid Bacteria but Act Synergistically with Gram-Negative Bacteria

    PubMed Central

    Zeuthen, Louise Hjerrild; Christensen, Hanne Risager; Frøkiær, Hanne

    2006-01-01

    The development and maintenance of immune homeostasis indispensably depend on signals from the gut flora. Lactic acid bacteria (LAB), which are gram-positive (G+) organisms, are plausible significant players and have received much attention. Gram-negative (G−) commensals, such as members of the family Enterobacteriaceae, may, however, be immunomodulators that are as important as G+ organisms but tend to be overlooked. Dendritic cells (DCs) are crucial immune regulators, and therefore, the present study aimed at investigating differences among human gut flora-derived LAB and G− bacteria in their patterns of DC polarization. Human monocyte-derived DCs were exposed to UV-killed bacteria, and cytokine secretion and surface marker expression were analyzed. Profound differences in the DC polarization patterns were found among the strains. While strains of LAB varied greatly in their capacity to induce interleukin-12 (IL-12) and tumor necrosis factor alpha (TNF-α), G− strains were consistently weak IL-12 and TNF-α inducers. All strains induced significant amounts of IL-10, but G− bacteria were far more potent IL-10 inducers than LAB. Interestingly, we found that when weakly IL-12- and TNF-α-inducing LAB and strong IL-12- and TNF-α-inducing LAB were mixed, the weakly IL-12- and TNF-α-inducing LAB efficiently inhibited otherwise strong IL-12- and TNF-α-inducing LAB, yet when weakly IL-12- and TNF-α-inducing LAB were mixed with G− bacteria, they synergistically induced IL-12 and TNF-α. Furthermore, strong IL-12- and TNF-α-inducing LAB efficiently up-regulated surface markers (CD40, CD83, CD86, and HLA-DR), which were inhibited by weakly IL-12- and TNF-α-inducing LAB. All G− bacteria potently up-regulated surface markers; however, these markers were not inhibited by weakly IL-12- and TNF-α-inducing LAB. These much divergent DC stimulation patterns among intestinal bacteria, which encompass both antagonistic and synergistic relationships, support the

  5. Canine Distemper Virus Infection Leads to an Inhibitory Phenotype of Monocyte-Derived Dendritic Cells In Vitro with Reduced Expression of Co-Stimulatory Molecules and Increased Interleukin-10 Transcription

    PubMed Central

    Herder, Vanessa; Stein, Veronika M.; Tipold, Andrea; Urhausen, Carola; Günzel-Apel, Anne-Rose; Rohn, Karl; Baumgärtner, Wolfgang; Beineke, Andreas

    2014-01-01

    Canine distemper virus (CDV) exhibits a profound lymphotropism that causes immunosuppression and increased susceptibility of affected dogs to opportunistic infections. Similar to human measles virus, CDV is supposed to inhibit terminal differentiation of dendritic cells (DCs), responsible for disturbed repopulation of lymphoid tissues and diminished antigen presenting function in dogs. In order to testify the hypothesis that CDV-infection leads to an impairment of professional antigen presenting cells, canine DCs have been generated from peripheral blood monocytes in vitro and infected with CDV. Virus infection was confirmed and quantified by transmission electron microscopy, CDV-specific immunofluorescence, and virus titration. Flow cytometric analyses revealed a significant down-regulation of the major histocompatibility complex class II and co-stimulatory molecules CD80 and CD86 in CDV-infected DCs, indicative of disturbed antigen presenting capacity. Molecular analyses revealed an increased expression of the immune inhibitory cytokine interleukin-10 in DCs following infection. Results of the present study demonstrate that CDV causes phenotypical changes and altered cytokine expression of DCs, which represent potential mechanisms to evade host immune responses and might contribute to immune dysfunction and virus persistence in canine distemper. PMID:24769532

  6. The regulation of 3-hydroxy-3-methylglutaryl-CoA reductase activity, cholesterol esterification and the expression of low-density lipoprotein receptors in cultured monocyte-derived macrophages.

    PubMed Central

    Knight, B L; Patel, D D; Soutar, A K

    1983-01-01

    Human blood monocytes cultured in medium containing 20% whole serum showed the greatest activity of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase and [14C]acetate incorporation into non-saponifiable lipids around the 7th day after seeding, the period of greatest growth. Although there was enough low-density lipoprotein (LDL) in the medium to saturate the LDL receptors that were expressed by normal cells at that time, HMG-CoA reductase activity and acetate incorporation were as high in normal cells as in cells from familial-hypercholesterolaemic (FH) patients. Both the addition of extra LDL, which interacted with the cells by non-saturable processes, and receptor-mediated uptake of acetylated LDL significantly reduced reductase activity and increased incorporation of [14C]oleate into cholesteryl esters in normal cells and cells from FH patients ('FH cells'), and reduced the expression of LDL receptors in normal cells. Pre-incubation for 20h in lipoprotein-deficient medium apparently increased the number of LDL receptors expressed by normal cells but reduced the activity of HMG-CoA reductase in both normal and FH cells. During subsequent incubations the same rate of degradation of acetylated LDL and of non-saturable degradation of LDL by FH cells was associated with the same reduction in HMG-CoA reductase activity, although LDL produced a much smaller stimulation of oleate incorporation into cholesteryl esters. In normal cells pre-incubated without lipoproteins, receptor-mediated uptake of LDL could abolish reductase activity and the expression of LDL receptors. The results suggested that in these cells, receptor-mediated uptake of LDL might have a greater effect on reductase activity and LDL receptors than the equivalent uptake of acetylated LDL. It is proposed that endogenous synthesis is an important source of cholesterol for growth of normal cells, and that the site at which cholesterol is deposited in the cells may determine the nature and extent of the metabolic events that follow. PMID:6305342

  7. Factor X deficiency

    MedlinePlus

    Factor X (ten) deficiency is a disorder caused by a lack of a protein called factor X in the blood. It leads to problems with ... or are not functioning like they should. Factor X is one such coagulation factor. Factor X deficiency ...

  8. Relationship of blood monocytes with chronic lymphocytic leukemia aggressiveness and outcomes: a multi-institutional study.

    PubMed

    Friedman, Daphne R; Sibley, Alexander B; Owzar, Kouros; Chaffee, Kari G; Slager, Susan; Kay, Neil E; Hanson, Curtis A; Ding, Wei; Shanafelt, Tait D; Weinberg, J Brice; Wilcox, Ryan A

    2016-07-01

    Monocyte-derived cells, constituents of the cancer microenvironment, support chronic lymphocytic leukemia (CLL) cell survival in vitro via direct cell-cell interaction and secreted factors. We hypothesized that circulating absolute monocyte count (AMC) reflects the monocyte-derived cells in the microenvironment, and that higher AMC is associated with increased CLL cell survival in vivo and thus inferior CLL patient outcomes. We assessed the extent to which AMC at diagnosis of CLL is correlated with clinical outcomes, and whether this information adds to currently used prognostic markers. We evaluated AMC, clinically used prognostic markers, and time to event data from 1,168 CLL patients followed at the Mayo Clinic, the Duke University Medical Center, and the Durham VA Medical Center. Elevated AMC was significantly associated with inferior clinical outcomes, including time to first therapy (TTT) and overall survival (OS). AMC combined with established clinical and molecular prognostic markers significantly improved risk-stratification of CLL patients for TTT. As an elevated AMC at diagnosis is associated with accelerated disease progression, and monocyte-derived cells in the CLL microenvironment promote CLL cell survival and proliferation, these findings suggest that monocytes and monocyte-derived cells are rational therapeutic targets in CLL. Am. J. Hematol. 91:687-691, 2016. © 2016 Wiley Periodicals, Inc. PMID:27037726

  9. ISS Payload Human Factors

    NASA Technical Reports Server (NTRS)

    Ellenberger, Richard; Duvall, Laura; Dory, Jonathan

    2016-01-01

    The ISS Payload Human Factors Implementation Team (HFIT) is the Payload Developer's resource for Human Factors. HFIT is the interface between Payload Developers and ISS Payload Human Factors requirements in SSP 57000. ? HFIT provides recommendations on how to meet the Human Factors requirements and guidelines early in the design process. HFIT coordinates with the Payload Developer and Astronaut Office to find low cost solutions to Human Factors challenges for hardware operability issues.

  10. Factor V deficiency

    MedlinePlus

    Blood clotting is a complex process involving as many as 20 different proteins in blood plasma. These proteins ... by a lack of Factor V. When certain blood clotting factors are low or missing, your blood does ...

  11. Factoring Polynomials and Fibonacci.

    ERIC Educational Resources Information Center

    Schwartzman, Steven

    1986-01-01

    Discusses the factoring of polynomials and Fibonacci numbers, offering several challenges teachers can give students. For example, they can give students a polynomial containing large numbers and challenge them to factor it. (JN)

  12. Factor VII deficiency

    MedlinePlus

    ... may be done include: Partial thromboplastin time ( PTT ) Plasma factor VII activity Prothrombin time ( PT ) Mixing study ... controlled by getting intravenous (IV) infusions of normal plasma, concentrates of factor VII, or genetically produced (recombinant) ...

  13. Heart disease - risk factors

    MedlinePlus

    ... medlineplus.gov/ency/patientinstructions/000106.htm Heart disease - risk factors To use the sharing features on this ... may help you live a longer, healthier life. Risk Factors You Cannot Change Some of your heart ...

  14. Factor V deficiency

    MedlinePlus

    ... as many as 20 different proteins in blood plasma. These proteins are called blood coagulation factors. Factor ... You will be given fresh blood plasma or fresh frozen plasma infusions ... These treatments will correct the deficiency temporarily.

  15. Mesonic Form Factors

    SciTech Connect

    Frederic D. R. Bonnet; Robert G. Edwards; George T. Fleming; Randal Lewis; David Richards

    2003-07-22

    We have started a program to compute the electromagnetic form factors of mesons. We discuss the techniques used to compute the pion form factor and present preliminary results computed with domain wall valence fermions on MILC asqtad lattices, as well as Wilson fermions on quenched lattices. These methods can easily be extended to rho-to-gamma-pi transition form factors.

  16. Multilevel Mixture Factor Models

    ERIC Educational Resources Information Center

    Varriale, Roberta; Vermunt, Jeroen K.

    2012-01-01

    Factor analysis is a statistical method for describing the associations among sets of observed variables in terms of a small number of underlying continuous latent variables. Various authors have proposed multilevel extensions of the factor model for the analysis of data sets with a hierarchical structure. These Multilevel Factor Models (MFMs)…

  17. Bayesian Exploratory Factor Analysis

    PubMed Central

    Conti, Gabriella; Frühwirth-Schnatter, Sylvia; Heckman, James J.; Piatek, Rémi

    2014-01-01

    This paper develops and applies a Bayesian approach to Exploratory Factor Analysis that improves on ad hoc classical approaches. Our framework relies on dedicated factor models and simultaneously determines the number of factors, the allocation of each measurement to a unique factor, and the corresponding factor loadings. Classical identification criteria are applied and integrated into our Bayesian procedure to generate models that are stable and clearly interpretable. A Monte Carlo study confirms the validity of the approach. The method is used to produce interpretable low dimensional aggregates from a high dimensional set of psychological measurements. PMID:25431517

  18. Aerostructural safety factor criteria

    NASA Technical Reports Server (NTRS)

    Verderaime, V.

    1992-01-01

    The present modification of the conventional safety factor method for aircraft structures evaluation involves the expression of deterministic safety factors in probabilistic tolerance limit ratios; these are found to involve a total of three factors that control the interference of applied and resistive stress distributions. The deterministic expression is extended so that it may furnish a 'relative ultimate safety' index that encompasses all three distribution factors. Operational reliability is developed on the basis of the applied and the yield stress distribution interferences. Industry standards are suggested to be derivable from factor selections that are based on the consequences of failure.

  19. Factor VIII and glomerulonephritis.

    PubMed

    Ekberg, M; Nilsson, I M

    1975-05-17

    To find out if determination of factor VIII,which most probably is synthetised in the intima of blood-vessesls, is of value for predicting the severity of vessel damge in glomerulonephritis, factor-VIII activity, factor-VIII-related antigen, and glomerular filtration-ratewere esto,ated om 85 patients with early glomerulonephritis on admission, and in 70 of these at follow-up for up to 4 years. The levels of factor-VIII activity and factor-VIII-related antigen on admission were normal in those patients who recovered. Where renal function was impaired on admission or becaome so during follow-up, factor VIII was high. Determination of factor VIII might thus be of prognostic value in early glomerulonephritis. PMID:49471

  20. New scale factor measure

    NASA Astrophysics Data System (ADS)

    Bousso, Raphael

    2012-07-01

    The computation of probabilities in an eternally inflating universe requires a regulator or “measure.” The scale factor time measure truncates the Universe when a congruence of timelike geodesics has expanded by a fixed volume factor. This definition breaks down if the generating congruence is contracting—a serious limitation that excludes from consideration gravitationally bound regions such as our own. Here we propose a closely related regulator which is well defined in the entire spacetime. The new scale factor cutoff restricts to events with a scale factor below a given value. Since the scale factor vanishes at caustics and crunches, this cutoff always includes an infinite number of disconnected future regions. We show that this does not lead to divergences. The resulting measure combines desirable features of the old scale factor cutoff and of the light-cone time cutoff, while eliminating some of the disadvantages of each.

  1. Analytic Couple Modeling Introducing Device Design Factor, Fin Factor, Thermal Diffusivity Factor, and Inductance Factor

    NASA Technical Reports Server (NTRS)

    Mackey, Jon; Sehirlioglu, Alp; Dynys, Fred

    2014-01-01

    A set of convenient thermoelectric device solutions have been derived in order to capture a number of factors which are previously only resolved with numerical techniques. The concise conversion efficiency equations derived from governing equations provide intuitive and straight-forward design guidelines. These guidelines allow for better device design without requiring detailed numerical modeling. The analytical modeling accounts for factors such as i) variable temperature boundary conditions, ii) lateral heat transfer, iii) temperature variable material properties, and iv) transient operation. New dimensionless parameters, similar to the figure of merit, are introduced including the device design factor, fin factor, thermal diffusivity factor, and inductance factor. These new device factors allow for the straight-forward description of phenomenon generally only captured with numerical work otherwise. As an example a device design factor of 0.38, which accounts for thermal resistance of the hot and cold shoes, can be used to calculate a conversion efficiency of 2.28 while the ideal conversion efficiency based on figure of merit alone would be 6.15. Likewise an ideal couple with efficiency of 6.15 will be reduced to 5.33 when lateral heat is accounted for with a fin factor of 1.0.

  2. Exploratory Bi-Factor Analysis

    ERIC Educational Resources Information Center

    Jennrich, Robert I.; Bentler, Peter M.

    2011-01-01

    Bi-factor analysis is a form of confirmatory factor analysis originally introduced by Holzinger. The bi-factor model has a general factor and a number of group factors. The purpose of this article is to introduce an exploratory form of bi-factor analysis. An advantage of using exploratory bi-factor analysis is that one need not provide a specific…

  3. FACTORS AFFECTING PITCH DISCRIMINATION.

    ERIC Educational Resources Information Center

    BERGAN, JOHN R.

    EFFECTS OF TONAL MEMORY OF TWO KINDS OF FACTORS WERE STUDIED. THE FACTORS WERE (1) THE CHARACTERISTICS OF STIMULI PRESENTED TO THE SUBJECT IN A PITCH IDENTIFICATION TASK, AND (2) THOSE EFFECTING THE RESPONSE THAT THE SUBJECT MAKES IN SUCH A TASK. FIVE HYPOTHESES WERE ADVANCED FOR STUDY. THE UNDERLYING ASSUMPTION WAS THAT THERE ARE IMPORTANT…

  4. Plant transcription factors.

    PubMed

    Meshi, T; Iwabuchi, M

    1995-12-01

    Transcriptional regulation of gene expression relies on the recognition of promoter elements by transcription factors. In the past several years, a considerable number of (putative) transcription factors have been identified in plants. Some genes coding for these factors were isolated by south-western screening with oligonucleotides as a probe or by homology-based screening, and others were initially isolated by genetic means and subsequently identified as the genes for transcription factors. These transcription factors often form families of structurally related proteins with similar DNA-binding specificities and in addition, they are sometimes involved in related phenomena. Some groups of factors homo- and/or heterodimerize to increase the length and variability of the target sequences. Transcriptional activators, in general, comprise a modular activation domain. The activities of the transcription factors are controlled by post-translational modification, like phosphorylation and glycosylation, as well as at the levels of nuclear transport, oligomerization, etc. In this review, we will summarize the current knowledge of plant transcription factors to help understand the mechanistic aspects of the transcriptional regulation of genes. PMID:8589926

  5. Factorizing RSA Keys

    NASA Astrophysics Data System (ADS)

    Blakey, Ed

    Factorization is notoriously difficult. Though the problem is not known to be NP-hard, neither efficient, algorithmic solution nor technologically practicable, quantum-computer solution has been found. This apparent complexity, which renders infeasible the factorization of sufficiently large values, makes secure the RSA cryptographic system.

  6. Block LU factorization

    NASA Technical Reports Server (NTRS)

    Demmel, James W.; Higham, Nicholas J.; Schreiber, Robert S.

    1992-01-01

    Many of the currently popular 'block algorithms' are scalar algorithms in which the operations have been grouped and reordered into matrix operations. One genuine block algorithm in practical use is block LU factorization, and this has recently been shown by Demmel and Higham to be unstable in general. It is shown here that block LU factorization is stable if A is block diagonally dominant by columns. Moreover, for a general matrix the level of instability in block LU factorization can be founded in terms of the condition number kappa(A) and the growth factor for Gaussian elimination without pivoting. A consequence is that block LU factorization is stable for a matrix A that is symmetric positive definite or point diagonally dominant by rows or columns as long as A is well-conditioned.

  7. Growth factors in haemopoiesis.

    PubMed

    Jones, A L; Millar, J L

    1989-01-01

    Haemopoietic growth factors have for over two decades allowed experimentalists to grow haemopoietic bone marrow cells in vitro. With refinements in technique and the discovery of novel growth factors, all of the known haemopoietic lineages can now be grown in vitro. This has allowed a much greater understanding of the complex process of haemopoiesis from the haemopoietic stem cell to the mature, functioning end-cell. The in vivo action of these growth factors has been harder to investigate. Although recombinant technology has afforded us the much greater quantities necessary for in vivo work, problems remain with administration because of effects on other tissues. Interpretation of results is difficult because of the complex inter-relationships which exist between factors. Some of these have been defined in vitro and it appears likely that they also operate in vivo. Erythropoietin is a physiological regulator of erythropoiesis. It has been detected in vivo with levels responding appropriately to stress (i.e. elevated in anaemia) and, when administered in pharmacological doses, has been shown to correct anaemia. Granulocyte/macrophage colony-stimulating factor (GM-CSF) has been detected in vivo and may influence the production and function of granulocytes and macrophages, although how it is regulated is unknown. Granulocyte colony-stimulating factor (G-CSF) and macrophage colony-stimulating factor are ore lineage-specific. Interleukin 3 (IL-3), although it has not been detected in vivo, may act on a primitive marrow precursor by expanding the population and making these cells more susceptible to other growth factors, such as GM-CSF. Interleukin 1 (IL-1) has been detected in vivo, does not appear to have any isolated action on bone marrow (except possibly radioprotection) but probably acts synergistically with other growth factors, such as G-CSF. Interleukins 2, 4, 5 and 6 have not been detected in vivo. All have effects on B-cells. In addition IL-2 is an essential

  8. Risk Factors for Tuberculosis

    PubMed Central

    Narasimhan, Padmanesan; Wood, James; MacIntyre, Chandini Raina; Mathai, Dilip

    2013-01-01

    The risk of progression from exposure to the tuberculosis bacilli to the development of active disease is a two-stage process governed by both exogenous and endogenous risk factors. Exogenous factors play a key role in accentuating the progression from exposure to infection among which the bacillary load in the sputum and the proximity of an individual to an infectious TB case are key factors. Similarly endogenous factors lead in progression from infection to active TB disease. Along with well-established risk factors (such as human immunodeficiency virus (HIV), malnutrition, and young age), emerging variables such as diabetes, indoor air pollution, alcohol, use of immunosuppressive drugs, and tobacco smoke play a significant role at both the individual and population level. Socioeconomic and behavioral factors are also shown to increase the susceptibility to infection. Specific groups such as health care workers and indigenous population are also at an increased risk of TB infection and disease. This paper summarizes these factors along with health system issues such as the effects of delay in diagnosis of TB in the transmission of the bacilli. PMID:23476764

  9. Environmental Factors in Autism

    PubMed Central

    Grabrucker, Andreas M.

    2013-01-01

    Autism is a neurodevelopmental disorders characterized by impairments in communication and social behavior, and by repetitive behaviors. Although genetic factors might be largely responsible for the occurrence of autism they cannot fully account for all cases and it is likely that in addition to a certain combination of autism-related genes, specific environmental factors might act as risk factors triggering the development of autism. Thus, the role of environmental factors in autism is an important area of research and recent data will be discussed in this review. Interestingly, the results show that many environmental risk factors are interrelated and their identification and comparison might unveil a common scheme of alterations on a contextual as well as molecular level. For example, both, disruption in the immune system and in zinc homeostasis may affect synaptic transmission in autism. Thus, here, a model is proposed that interconnects the most important and scientifically recognized environmental factors. Moreover, similarities in how these risk factors impact synapse function are discussed and a possible influence on an already well described genetic pathway leading to the development of autism via zinc homeostasis is proposed. PMID:23346059

  10. Precipitating factors of insomnia.

    PubMed

    Bastien, Célyne H; Vallières, Annie; Morin, Charles M

    2004-01-01

    Insomnia is a prevalent health complaint whose onset is precipitated by a variety of factors. There is an important need to identify and describe these factors to improve our understanding of risk factors and the natural history of insomnia. This article is aimed at identifying and describing the types of precipitating factors related to the onset of insomnia. A total of 345 patients evaluated for insomnia at a sleep-disorders clinic completed a sleep survey and underwent a semistructured clinical interview. As part of the evaluation, the specific precipitating events related to the onset of insomnia were identified. Subsequently, these factors were categorized (work-school, family, physical or psychological health, or indeterminate), and their affective valence (negative, positive, or indeterminate) was coded. The most common precipitating factors of insomnia were related to family, health, and work-school events. Sixty-five percent of precipitating events had a negative valence. These events differed with the age of onset of insomnia but not with the gender of participants. These findings are useful to identify potential risk factors for insomnia and improve our understanding of the natural history of insomnia. PMID:15600224

  11. Conundrums with uncertainty factors.

    PubMed

    Cooke, Roger

    2010-03-01

    The practice of uncertainty factors as applied to noncancer endpoints in the IRIS database harkens back to traditional safety factors. In the era before risk quantification, these were used to build in a "margin of safety." As risk quantification takes hold, the safety factor methods yield to quantitative risk calculations to guarantee safety. Many authors believe that uncertainty factors can be given a probabilistic interpretation as ratios of response rates, and that the reference values computed according to the IRIS methodology can thus be converted to random variables whose distributions can be computed with Monte Carlo methods, based on the distributions of the uncertainty factors. Recent proposals from the National Research Council echo this view. Based on probabilistic arguments, several authors claim that the current practice of uncertainty factors is overprotective. When interpreted probabilistically, uncertainty factors entail very strong assumptions on the underlying response rates. For example, the factor for extrapolating from animal to human is the same whether the dosage is chronic or subchronic. Together with independence assumptions, these assumptions entail that the covariance matrix of the logged response rates is singular. In other words, the accumulated assumptions entail a log-linear dependence between the response rates. This in turn means that any uncertainty analysis based on these assumptions is ill-conditioned; it effectively computes uncertainty conditional on a set of zero probability. The practice of uncertainty factors is due for a thorough review. Two directions are briefly sketched, one based on standard regression models, and one based on nonparametric continuous Bayesian belief nets. PMID:20030767

  12. Rheumatoid factor (RF)

    MedlinePlus

    Rheumatoid factor (RF) is a blood test that measures the amount of the RF antibody in the blood. ... these conditions still have a "normal" or low RF. Normal value ranges may vary slightly among different ...

  13. Aerospace Human Factors

    NASA Technical Reports Server (NTRS)

    Jordan, Kevin

    1999-01-01

    The following contains the final report on the activities related to the Cooperative Agreement between the human factors research group at NASA Ames Research Center and the Psychology Department at San Jose State University. The participating NASA Ames division has been, as the organization has changed, the Aerospace Human Factors Research Division (ASHFRD and Code FL), the Flight Management and Human Factors Research Division (Code AF), and the Human Factors Research and Technology Division (Code IH). The inclusive dates for the report are November 1, 1984 to January 31, 1999. Throughout the years, approximately 170 persons worked on the cooperative agreements in one capacity or another. The Cooperative Agreement provided for research personnel to collaborate with senior scientists in ongoing NASA ARC research. Finally, many post-MA/MS and post-doctoral personnel contributed to the projects. It is worth noting that 10 former cooperative agreement personnel were hired into civil service positions directly from the agreements.

  14. von Willebrand Factor Test

    MedlinePlus

    ... Platelet Count , Platelet Function Tests , Complete Blood Count , Coagulation Factor VIII , PT , PTT At a Glance Test ... a protein , one of several components of the coagulation system that work together to stop bleeding and ...

  15. Factor II deficiency

    MedlinePlus

    ... blood. It leads to problems with blood clotting (coagulation). Factor II is also known as prothrombin. ... blood clots form. This process is called the coagulation cascade. It involves special proteins called coagulation, or ...

  16. Factors Affecting Wound Healing

    PubMed Central

    Guo, S.; DiPietro, L.A.

    2010-01-01

    Wound healing, as a normal biological process in the human body, is achieved through four precisely and highly programmed phases: hemostasis, inflammation, proliferation, and remodeling. For a wound to heal successfully, all four phases must occur in the proper sequence and time frame. Many factors can interfere with one or more phases of this process, thus causing improper or impaired wound healing. This article reviews the recent literature on the most significant factors that affect cutaneous wound healing and the potential cellular and/or molecular mechanisms involved. The factors discussed include oxygenation, infection, age and sex hormones, stress, diabetes, obesity, medications, alcoholism, smoking, and nutrition. A better understanding of the influence of these factors on repair may lead to therapeutics that improve wound healing and resolve impaired wounds. PMID:20139336

  17. New microbial growth factor

    NASA Technical Reports Server (NTRS)

    Bok, S. H.; Casida, L. E., Jr.

    1977-01-01

    A screening procedure was used to isolate from soil a Penicillium sp., two bacterial isolates, and a Streptomyces sp. that produced a previously unknown microbial growth factor. This factor was an absolute growth requirement for three soil bacteria. The Penicillium sp. and one of the bacteria requiring the factor, an Arthrobacter sp., were selected for more extensive study concerning the production and characteristics of the growth factor. It did not seem to be related to the siderochromes. It was not present in soil extract, rumen fluid, or any other medium component tested. It appears to be a glycoprotein of high molecular weight and has high specific activity. When added to the diets for a meadow-vole mammalian test system, it caused an increased consumption of diet without a concurrent increase in rate of weight gain.

  18. Automated Factor Slice Sampling.

    PubMed

    Tibbits, Matthew M; Groendyke, Chris; Haran, Murali; Liechty, John C

    2014-01-01

    Markov chain Monte Carlo (MCMC) algorithms offer a very general approach for sampling from arbitrary distributions. However, designing and tuning MCMC algorithms for each new distribution, can be challenging and time consuming. It is particularly difficult to create an efficient sampler when there is strong dependence among the variables in a multivariate distribution. We describe a two-pronged approach for constructing efficient, automated MCMC algorithms: (1) we propose the "factor slice sampler", a generalization of the univariate slice sampler where we treat the selection of a coordinate basis (factors) as an additional tuning parameter, and (2) we develop an approach for automatically selecting tuning parameters in order to construct an efficient factor slice sampler. In addition to automating the factor slice sampler, our tuning approach also applies to the standard univariate slice samplers. We demonstrate the efficiency and general applicability of our automated MCMC algorithm with a number of illustrative examples. PMID:24955002

  19. Automated Factor Slice Sampling

    PubMed Central

    Tibbits, Matthew M.; Groendyke, Chris; Haran, Murali; Liechty, John C.

    2013-01-01

    Markov chain Monte Carlo (MCMC) algorithms offer a very general approach for sampling from arbitrary distributions. However, designing and tuning MCMC algorithms for each new distribution, can be challenging and time consuming. It is particularly difficult to create an efficient sampler when there is strong dependence among the variables in a multivariate distribution. We describe a two-pronged approach for constructing efficient, automated MCMC algorithms: (1) we propose the “factor slice sampler”, a generalization of the univariate slice sampler where we treat the selection of a coordinate basis (factors) as an additional tuning parameter, and (2) we develop an approach for automatically selecting tuning parameters in order to construct an efficient factor slice sampler. In addition to automating the factor slice sampler, our tuning approach also applies to the standard univariate slice samplers. We demonstrate the efficiency and general applicability of our automated MCMC algorithm with a number of illustrative examples. PMID:24955002

  20. FGF growth factor analogs

    DOEpatents

    Zamora, Paul O.; Pena, Louis A.; Lin, Xinhua; Takahashi, Kazuyuki

    2012-07-24

    The present invention provides a fibroblast growth factor heparin-binding analog of the formula: ##STR00001## where R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, X, Y and Z are as defined, pharmaceutical compositions, coating compositions and medical devices including the fibroblast growth factor heparin-binding analog of the foregoing formula, and methods and uses thereof.

  1. A load factor formula

    NASA Technical Reports Server (NTRS)

    Miller, Roy G

    1927-01-01

    The ultimate test of a load factor formula is experience. The chief advantages of a semi rational formula over arbitrary factors are that it fairs in between points of experience and it differentiates according to variables within a type. Structural failure of an airplane apparently safe according to the formula would call for a specific change in the formula. The best class of airplanes with which to check a load factor formula seems to be those which have experienced structural failure. Table I comprises a list of the airplanes which have experienced failure in flight traceable to the wing structure. The load factor by formula is observed to be greater than the designed strength in each case, without a single exception. Table II comprises the load factor by formula with the designed strength of a number of well-known service types. The formula indicates that by far the majority of these have ample structural strength. One case considered here in deriving a suitable formula is that of a heavy load carrier of large size and practically no reserve power.

  2. Power Factor Controller Study.

    SciTech Connect

    Knudson Engineers, Inc.

    1989-08-01

    The complete report is divided into three parts as follows: (1) This report combines a historical perspective with a current assessment of the use of power factor controllers for three-phase ac motor energy savings. The power factor controller (PFC) is a power electronics device that reduces voltage to a motor during periods of reduced motor torque requirements. (2) A power factor controller (PFC) is a power electronics device that reduces voltage to a motor during periods of reduced motor torque requirements. This report is the DEMONSTRATION phase of the PFC study. The phase report consists of three task reports -- Site Selection, Demonstration Preparation, and Demonstration. The reports explain how three sites were selected for demonstration, describe what was measured at each site and the method of measurement, and compare measured energy savings with calculated predictions of energy savings. The report concludes that PFCs can save energy on carefully selected motor applications. (3) The results of the demonstration task are described in this report. A power factor controller (PFC) is a power electronics device that reduces voltage to a motor during periods of reduced motor torque requirements. The demonstration phase of this study calculates projected energy savings with the use of a PFC and compares measured performance with the calculations. The effect of the PFC on motor power requirements, power factor and energy consumption shall be measured.

  3. Breast cancer risk factors

    PubMed Central

    Ciszewski, Tomasz; Łopacka-Szatan, Karolina; Miotła, Paweł; Starosławska, Elżbieta

    2015-01-01

    Breast cancer is the most frequently diagnosed neoplastic disease in women around menopause often leading to a significant reduction of these women's ability to function normally in everyday life. The increased breast cancer incidence observed in epidemiological studies in a group of women actively participating in social and professional life implicates the necessity of conducting multidirectional studies in order to identify risk factors associated with the occurrence of this type of neoplasm. Taking the possibility of influencing the neoplastic transformation process in individuals as a criterion, all the risk factors initiating the process can be divided into two groups. The first group would include inherent factors such as age, sex, race, genetic makeup promoting familial occurrence of the neoplastic disease or the occurrence of benign proliferative lesions of the mammary gland. They all constitute independent parameters and do not undergo simple modification in the course of an individual's life. The second group would include extrinsic factors conditioned by lifestyle, diet or long-term medical intervention such as using oral hormonal contraceptives or hormonal replacement therapy and their influence on the neoplastic process may be modified to a certain degree. Identification of modifiable factors may contribute to development of prevention strategies decreasing breast cancer incidence. PMID:26528110

  4. Electromagnetic nucleon form factors

    SciTech Connect

    Bender, A.; Roberts, C.D.; Frank, M.R.

    1995-08-01

    The Dyson-Schwinger equation framework is employed to obtain expressions for the electromagnetic nucleon form factor. In generalized impulse approximation the form factor depends on the dressed quark propagator, the dressed quark-photon vertex, which is crucial to ensuring current conservation, and the nucleon Faddeev amplitude. The approach manifestly incorporates the large space-like-q{sup 2} renormalization group properties of QCD and allows a realistic extrapolation to small space-like-q{sup 2}. This extrapolation allows one to relate experimental data to the form of the quark-quark interaction at small space-like-q{sup 2}, which is presently unknown. The approach provides a means of unifying, within a single framework, the treatment of the perturbative and nonperturbative regimes of QCD. The wealth of experimental nucleon form factor data, over a large range of q{sup 2}, ensures that this application will provide an excellent environment to test, improve and extend our approach.

  5. Geothermal Plant Capacity Factors

    SciTech Connect

    Greg Mines; Jay Nathwani; Christopher Richard; Hillary Hanson; Rachel Wood

    2015-01-01

    The capacity factors recently provided by the Energy Information Administration (EIA) indicated this plant performance metric had declined for geothermal power plants since 2008. Though capacity factor is a term commonly used by geothermal stakeholders to express the ability of a plant to produce power, it is a term frequently misunderstood and in some instances incorrectly used. In this paper we discuss how this capacity factor is defined and utilized by the EIA, including discussion on the information that the EIA requests from operations in their 923 and 860 forms that are submitted both monthly and annually by geothermal operators. A discussion is also provided regarding the entities utilizing the information in the EIA reports, and how those entities can misinterpret the data being supplied by the operators. The intent of the paper is to inform the facility operators as the importance of the accuracy of the data that they provide, and the implications of not providing the correct information.

  6. Psychological Factors in Asthma

    PubMed Central

    2008-01-01

    Asthma has long been considered a condition in which psychological factors have a role. As in many illnesses, psychological variables may affect outcome in asthma via their effects on treatment adherence and symptom reporting. Emerging evidence suggests that the relation between asthma and psychological factors may be more complex than that, however. Central cognitive processes may influence not only the interpretation of asthma symptoms but also the manifestation of measurable changes in immune and physiologic markers of asthma. Furthermore, asthma and major depressive disorder share several risk factors and have similar patterns of dysregulation in key biologic systems, including the neuroendocrine stress response, cytokines, and neuropeptides. Despite the evidence that depression is common in people with asthma and exerts a negative impact on outcome, few treatment studies have examined whether improving symptoms of depression do, in fact, result in better control of asthma symptoms or improved quality of life in patients with asthma. PMID:20525122

  7. DSN human factors project

    NASA Technical Reports Server (NTRS)

    Chafin, R. L.; Martin, T. H.

    1980-01-01

    The project plan was to hold focus groups to identify the factors influencing the ease of use characteristics of software and to bond the problem. A questionnaire survey was conducted to evaluate those factors which were more appropriately measured with that method. The performance oriented factors were analyzed and relationships hypothesized. The hypotheses were put to test in the experimental phase of the project. In summary, the initial analysis indicates that there is an initial performance effect favoring computer controlled dialogue but the advantage fades fast as operators become experienced. The user documentation style is seen to have a significant effect on performance. The menu and prompt command formats are preferred by inexperienced operators. The short form mnemonic is least favored. There is no clear best command format but the short form mnemonic is clearly the worst.

  8. Multi-factor authentication

    SciTech Connect

    Hamlet, Jason R; Pierson, Lyndon G

    2014-10-21

    Detection and deterrence of spoofing of user authentication may be achieved by including a cryptographic fingerprint unit within a hardware device for authenticating a user of the hardware device. The cryptographic fingerprint unit includes an internal physically unclonable function ("PUF") circuit disposed in or on the hardware device, which generates a PUF value. Combining logic is coupled to receive the PUF value, combines the PUF value with one or more other authentication factors to generate a multi-factor authentication value. A key generator is coupled to generate a private key and a public key based on the multi-factor authentication value while a decryptor is coupled to receive an authentication challenge posed to the hardware device and encrypted with the public key and coupled to output a response to the authentication challenge decrypted with the private key.

  9. WRKY transcription factors

    PubMed Central

    Bakshi, Madhunita; Oelmüller, Ralf

    2014-01-01

    WRKY transcription factors are one of the largest families of transcriptional regulators found exclusively in plants. They have diverse biological functions in plant disease resistance, abiotic stress responses, nutrient deprivation, senescence, seed and trichome development, embryogenesis, as well as additional developmental and hormone-controlled processes. WRKYs can act as transcriptional activators or repressors, in various homo- and heterodimer combinations. Here we review recent progress on the function of WRKY transcription factors in Arabidopsis and other plant species such as rice, potato, and parsley, with a special focus on abiotic, developmental, and hormone-regulated processes. PMID:24492469

  10. Anti-nutritional Factors.

    PubMed

    2016-01-01

    Anti-nutritional factors such as trypsin inhibitor, phytic acid and cyanogen are as important as nutritional content of any edible plant part. The anti-nutritional factors can be defined as those substances generated in natural food substances by the normal metabolism of species and by different mechanisms (e.g. inactivation of some nutrients, diminution of the digestive process or metabolic utilization of feed) which exert effects contrary to optimum nutrition. Hence, trypsin inhibitor, phytic acid and cyanogens present in edibles with the methods in the chapter would be helpful. PMID:26939264

  11. Factor D Enzyme

    NASA Technical Reports Server (NTRS)

    2004-01-01

    The trauma caused by the open heart surgery often triggers massive inflammation because the immune system overreacts. Factor D, the protein which plays a key role in the biological steps that activate this immune response prevents the imune system from inappropriately rurning out of control, allowing the patient to recover more rapidly. Factor D blockers, with their great potential to alleviate the complication of inflammation associated with heart surgery, are now being developed for clinical trials. These new drugs, developed from space research, should be commercially available as soon as year 2001.

  12. The Transcription Factor Encyclopedia

    PubMed Central

    2012-01-01

    Here we present the Transcription Factor Encyclopedia (TFe), a new web-based compendium of mini review articles on transcription factors (TFs) that is founded on the principles of open access and collaboration. Our consortium of over 100 researchers has collectively contributed over 130 mini review articles on pertinent human, mouse and rat TFs. Notable features of the TFe website include a high-quality PDF generator and web API for programmatic data retrieval. TFe aims to rapidly educate scientists about the TFs they encounter through the delivery of succinct summaries written and vetted by experts in the field. TFe is available at http://www.cisreg.ca/tfe. PMID:22458515

  13. Radiative Gaunt factors

    NASA Astrophysics Data System (ADS)

    Burgess, Alan; Summers, Hugh P.

    1987-05-01

    Numerical methods for the evaluation of radiative Gaunt factors for complex ions, and for the calculation of the principal integrals over the Gaunt factors relevant to plasma spectroscopy, are presented. The present techniques are suitable for the computation of intermediate accuracy results for large numbers of ions over extended parameter ranges, and they cover bound-bound, bound-free, and free-free cases in both hydrogenic and nonhydrogenic approximations. The results demonstrate the reliability of the numerical methods and their advantages over the methods of Peach (1965, 1967) and Burgess and Seaton (1960). Significant differences from hydrogenic results at low and moderate z values are pointed out.

  14. The transcription factor encyclopedia.

    PubMed

    Yusuf, Dimas; Butland, Stefanie L; Swanson, Magdalena I; Bolotin, Eugene; Ticoll, Amy; Cheung, Warren A; Zhang, Xiao Yu Cindy; Dickman, Christopher T D; Fulton, Debra L; Lim, Jonathan S; Schnabl, Jake M; Ramos, Oscar H P; Vasseur-Cognet, Mireille; de Leeuw, Charles N; Simpson, Elizabeth M; Ryffel, Gerhart U; Lam, Eric W-F; Kist, Ralf; Wilson, Miranda S C; Marco-Ferreres, Raquel; Brosens, Jan J; Beccari, Leonardo L; Bovolenta, Paola; Benayoun, Bérénice A; Monteiro, Lara J; Schwenen, Helma D C; Grontved, Lars; Wederell, Elizabeth; Mandrup, Susanne; Veitia, Reiner A; Chakravarthy, Harini; Hoodless, Pamela A; Mancarelli, M Michela; Torbett, Bruce E; Banham, Alison H; Reddy, Sekhar P; Cullum, Rebecca L; Liedtke, Michaela; Tschan, Mario P; Vaz, Michelle; Rizzino, Angie; Zannini, Mariastella; Frietze, Seth; Farnham, Peggy J; Eijkelenboom, Astrid; Brown, Philip J; Laperrière, David; Leprince, Dominique; de Cristofaro, Tiziana; Prince, Kelly L; Putker, Marrit; del Peso, Luis; Camenisch, Gieri; Wenger, Roland H; Mikula, Michal; Rozendaal, Marieke; Mader, Sylvie; Ostrowski, Jerzy; Rhodes, Simon J; Van Rechem, Capucine; Boulay, Gaylor; Olechnowicz, Sam W Z; Breslin, Mary B; Lan, Michael S; Nanan, Kyster K; Wegner, Michael; Hou, Juan; Mullen, Rachel D; Colvin, Stephanie C; Noy, Peter John; Webb, Carol F; Witek, Matthew E; Ferrell, Scott; Daniel, Juliet M; Park, Jason; Waldman, Scott A; Peet, Daniel J; Taggart, Michael; Jayaraman, Padma-Sheela; Karrich, Julien J; Blom, Bianca; Vesuna, Farhad; O'Geen, Henriette; Sun, Yunfu; Gronostajski, Richard M; Woodcroft, Mark W; Hough, Margaret R; Chen, Edwin; Europe-Finner, G Nicholas; Karolczak-Bayatti, Magdalena; Bailey, Jarrod; Hankinson, Oliver; Raman, Venu; LeBrun, David P; Biswal, Shyam; Harvey, Christopher J; DeBruyne, Jason P; Hogenesch, John B; Hevner, Robert F; Héligon, Christophe; Luo, Xin M; Blank, Marissa Cathleen; Millen, Kathleen Joyce; Sharlin, David S; Forrest, Douglas; Dahlman-Wright, Karin; Zhao, Chunyan; Mishima, Yuriko; Sinha, Satrajit; Chakrabarti, Rumela; Portales-Casamar, Elodie; Sladek, Frances M; Bradley, Philip H; Wasserman, Wyeth W

    2012-01-01

    Here we present the Transcription Factor Encyclopedia (TFe), a new web-based compendium of mini review articles on transcription factors (TFs) that is founded on the principles of open access and collaboration. Our consortium of over 100 researchers has collectively contributed over 130 mini review articles on pertinent human, mouse and rat TFs. Notable features of the TFe website include a high-quality PDF generator and web API for programmatic data retrieval. TFe aims to rapidly educate scientists about the TFs they encounter through the delivery of succinct summaries written and vetted by experts in the field. TFe is available at http://www.cisreg.ca/tfe. PMID:22458515

  15. Radiation View Factor With Shadowing

    Energy Science and Technology Software Center (ESTSC)

    1992-02-24

    FACET calculates the radiation geometric view factor (alternatively called shape factor, angle factor, or configuration factor) between surfaces for axisymmetric, two-dimensional planar and three-dimensional geometries with interposed third surface obstructions. FACET was developed to calculate view factors as input data to finite element heat transfer analysis codes.

  16. Factor Analysis and Counseling Research

    ERIC Educational Resources Information Center

    Weiss, David J.

    1970-01-01

    Topics discussed include factor analysis versus cluster analysis, analysis of Q correlation matrices, ipsativity and factor analysis, and tests for the significance of a correlation matrix prior to application of factor analytic techniques. Techniques for factor extraction discussed include principal components, canonical factor analysis, alpha…

  17. Lentiviral Vpx Accessory Factor Targets VprBP/DCAF1 Substrate Adaptor for Cullin 4 E3 Ubiquitin Ligase to Enable Macrophage Infection

    PubMed Central

    Srivastava, Smita; Swanson, Selene K.; Manel, Nicolas; Florens, Laurence; Washburn, Michael P.; Skowronski, Jacek

    2008-01-01

    Vpx is a small virion-associated adaptor protein encoded by viruses of the HIV-2/SIVsm lineage of primate lentiviruses that enables these viruses to transduce monocyte-derived cells. This probably reflects the ability of Vpx to overcome an as yet uncharacterized block to an early event in the virus life cycle in these cells, but the underlying mechanism has remained elusive. Using biochemical and proteomic approaches, we have found that Vpx protein of the pathogenic SIVmac 239 strain associates with a ternary protein complex comprising DDB1 and VprBP subunits of Cullin 4–based E3 ubiquitin ligase, and DDA1, which has been implicated in the regulation of E3 catalytic activity, and that Vpx participates in the Cullin 4 E3 complex comprising VprBP. We further demonstrate that the ability of SIVmac as well as HIV-2 Vpx to interact with VprBP and its associated Cullin 4 complex is required for efficient reverse transcription of SIVmac RNA genome in primary macrophages. Strikingly, macrophages in which VprBP levels are depleted by RNA interference resist SIVmac infection. Thus, our observations reveal that Vpx interacts with both catalytic and regulatory components of the ubiquitin proteasome system and demonstrate that these interactions are critical for Vpx ability to enable efficient SIVmac replication in primary macrophages. Furthermore, they identify VprBP/DCAF1 substrate receptor for Cullin 4 E3 ubiquitin ligase and its associated protein complex as immediate downstream effector of Vpx for this function. Together, our findings suggest a model in which Vpx usurps VprBP-associated Cullin 4 ubiquitin ligase to enable efficient reverse transcription and thereby overcome a block to lentivirus replication in monocyte-derived cells, and thus provide novel insights into the underlying molecular mechanism. PMID:18464893

  18. Affective Factors: Anxiety

    ERIC Educational Resources Information Center

    Tasnimi, Mahshad

    2009-01-01

    Affective factors seem to play a crucial role in success or failure in second language acquisition. Negative attitudes can reduce learners' motivation and harm language learning, while positive attitudes can do the reverse. Discovering students' attitudes about language will help both teacher and student in teaching learning process. Anxiety is…

  19. Assessment of Human Factors

    NASA Technical Reports Server (NTRS)

    Mount, Frances; Foley, Tico

    1999-01-01

    Human Factors Engineering, often referred to as Ergonomics, is a science that applies a detailed understanding of human characteristics, capabilities, and limitations to the design, evaluation, and operation of environments, tools, and systems for work and daily living. Human Factors is the investigation, design, and evaluation of equipment, techniques, procedures, facilities, and human interfaces, and encompasses all aspects of human activity from manual labor to mental processing and leisure time enjoyments. In spaceflight applications, human factors engineering seeks to: (1) ensure that a task can be accomplished, (2) maintain productivity during spaceflight, and (3) ensure the habitability of the pressurized living areas. DSO 904 served as a vehicle for the verification and elucidation of human factors principles and tools in the microgravity environment. Over six flights, twelve topics were investigated. This study documented the strengths and limitations of human operators in a complex, multifaceted, and unique environment. By focusing on the man-machine interface in space flight activities, it was determined which designs allow astronauts to be optimally productive during valuable and costly space flights. Among the most promising areas of inquiry were procedures, tools, habitat, environmental conditions, tasking, work load, flexibility, and individual control over work.

  20. Introduction to human factors

    SciTech Connect

    Winters, J.M.

    1988-03-01

    Some background is given on the field of human factors. The nature of problems with current human/computer interfaces is discussed, some costs are identified, ideal attributes of graceful system interfaces are outlined, and some reasons are indicated why it's not easy to fix the problems. (LEW)

  1. ERYTHROPOIETIC FACTOR PURIFICATION

    DOEpatents

    White, W.F.; Schlueter, R.J.

    1962-05-01

    A method is given for purifying and concentrating the blood plasma erythropoietic factor. Anemic sheep plasma is contacted three times successively with ion exchange resins: an anion exchange resin, a cation exchange resin at a pH of about 5, and a cation exchange resin at a pH of about 6. (AEC)

  2. Thyroid Cancer Risk Factors

    MedlinePlus

    ... and radiation fallout from power plant accidents or nuclear weapons. Having had head or neck radiation treatments in childhood is a risk factor for ... should be done using the lowest dose of radiation that still provides a clear ... from nuclear weapons or power plant accidents. For instance, thyroid ...

  3. Common conversion factors.

    PubMed

    2001-05-01

    This appendix presents tables of some of the more common conversion factors for units of measure used throughout Current Protocols manuals, as well as prefixes indicating powers of ten for SI units. Another table gives conversions between temperatures on the Celsius (Centigrade) and Fahrenheit scales. PMID:18770653

  4. Inelastic Scattering Form Factors

    Energy Science and Technology Software Center (ESTSC)

    1992-01-01

    ATHENA-IV computes form factors for inelastic scattering calculations, using single-particle wave functions that are eigenstates of motion in either a Woods-Saxon potential well or a harmonic oscillator well. Two-body forces of Gauss, Coulomb, Yukawa, and a sum of cut-off Yukawa radial dependences are available.

  5. Recombinant factor VIIa.

    PubMed

    Aitken, Michael G

    2004-01-01

    Human coagulation factor (F) VII is a single chain protease that circulates in the blood as a weakly active zymogen at concentrations of approximately 10 nmol/L. When converted to the active 2 chain form (FVIIa), it is a powerful initiator of haemostasis. Recombinant factor VIIa (rFVIIa, eptacog alfa, NovoSeven) is a genetically engineered product that was first introduced in 1988 for the treatment of patients with haemophilia A and B with high inhibitory antibody titres to factors VIII and IX. Recent reports in the form of case studies and series, and early trial data, have suggested a role for rFVIIa across a diverse range of indications including bleeding associated with trauma, surgery, thrombocytopaenia, liver disease and oral anticoagulant toxicity. This review describes the physiology of the coagulation pathway and in particular the role of recombinant factor VIIa. It will also focus on the emerging role of rFVIIa in both trauma and non-trauma bleeding and its potential use in the ED. PMID:15537408

  6. Peptide growth factors, part B

    SciTech Connect

    Barnes, D.; Sirbasku, D.A.

    1987-01-01

    This book discusses the following topics: Platelet-Derived Growth Factor;Nerve and Glial Growth Factors;PC12 Pheochromocytoma Cells;Techniques for the Study of Growth Factor Activity;Genetic Approaches and Biological Effects.

  7. Factor structure of nonverbal cognition.

    PubMed

    Ardil, A; Pineda, D A

    2000-01-01

    In order to define the factor structure of nonverbal cognitive processes, 156 twenty to sixty year-old participants were selected in Medellin (Colombia). A neuropsychological test battery for assessing different nonverbal cognitive domains (attention, memory, visuoperceptual and visuoconstructive abilities. executive functions, praxis abilities, and written calculation abilities) was administered. Initially, independent factor analyses were carried out for each domain. Three attention factors (Sustained Attention, Divided Attention, and Processing Speed, 73.1% of the variance); two memory factors (Categorical and Non-Categorical Memory, 59.7% of the variance): two visuoperceptual and visuoconstructive factors (Sequential and Simultaneous, 54.0% of the variance); and two executive function factors (Categorization and Trial Error, 82.0% of the variance) were found. Further, several sequential factor analyses using Varimax orthogonal rotations for noncorrelated variables were performed. The 32 test variables were included, but progressively some variables were removed. This procedure finally selected 13 variables corresponding to five factors accounting for 72.6% of variance. Factor I was an Executive Function factor (30% of variance). Factor 2 corresponded to a Sequential Constructional factor (14.7%). Factor 3 represented a Processing Speed factor and accounted for 10.6% of the variance. Factor 4 was Visuoperceptual factor (9.5% of the variance). Finally, Factor 5 (7.8% of the variance) was a Nonverbal Memory factor. It was concluded that several, different cognitive dimensions are included in nonverbal cognition. PMID:11011978

  8. Human factors workplace considerations

    NASA Technical Reports Server (NTRS)

    Haines, Richard F.

    1988-01-01

    Computer workstations assume many different forms and play different functions today. In order for them to assume the effective interface role which they should play they must be properly designed to take into account the ubiguitous human factor. In addition, the entire workplace in which they are used should be properly configured so as to enhance the operational features of the individual workstation where possible. A number of general human factors workplace considerations are presented. This ongoing series of notes covers such topics as achieving comfort and good screen visibility, hardware issues (e.g., mouse maintenance), screen symbology features (e.g., labels, cursors, prompts), and various miscellaneous subjects. These notes are presented here in order to: (1) illustrate how one's workstation can be used to support telescience activities of many other people working within an organization, and (2) provide a single complete set of considerations for future reference.

  9. Helicopter human factors

    NASA Technical Reports Server (NTRS)

    Hart, Sandra G.

    1988-01-01

    The state-of-the-art helicopter and its pilot are examined using the tools of human-factors analysis. The significant role of human error in helicopter accidents is discussed; the history of human-factors research on helicopters is briefly traced; the typical flight tasks are described; and the noise, vibration, and temperature conditions typical of modern military helicopters are characterized. Also considered are helicopter controls, cockpit instruments and displays, and the impact of cockpit design on pilot workload. Particular attention is given to possible advanced-technology improvements, such as control stabilization and augmentation, FBW and fly-by-light systems, multifunction displays, night-vision goggles, pilot night-vision systems, night-vision displays with superimposed symbols, target acquisition and designation systems, and aural displays. Diagrams, drawings, and photographs are provided.

  10. [Streptococcus pyogenes pathogenic factors].

    PubMed

    Bidet, Ph; Bonacorsi, S

    2014-11-01

    The pathogenicity of ß-hemolytic group A streptococcus (GAS) is particularly diverse, ranging from mild infections, such as pharyngitis or impetigo, to potentially debilitating poststreptococcal diseases, and up to severe invasive infections such as necrotizing fasciitis or the dreaded streptococcal toxic shock syndrome. This variety of clinical expressions, often radically different in individuals infected with the same strain, results from a complex interaction between the bacterial virulence factors, the mode of infection and the immune system of the host. Advances in comparative genomics have led to a better understanding of how, following this confrontation, GAS adapts to the immune system's pressure, either peacefully by reducing the expression of certain virulence factors to achieve an asymptomatic carriage, or on the contrary, by overexpressing them disproportionately, resulting in the most severe forms of invasive infection. PMID:25456681

  11. Factors regulating microglia activation

    PubMed Central

    Kierdorf, Katrin; Prinz, Marco

    2013-01-01

    Microglia are resident macrophages of the central nervous system (CNS) that display high functional similarities to other tissue macrophages. However, it is especially important to create and maintain an intact tissue homeostasis to support the neuronal cells, which are very sensitive even to minor changes in their environment. The transition from the “resting” but surveying microglial phenotype to an activated stage is tightly regulated by several intrinsic (e.g., Runx-1, Irf8, and Pu.1) and extrinsic factors (e.g., CD200, CX3CR1, and TREM2). Under physiological conditions, minor changes of those factors are sufficient to cause fatal dysregulation of microglial cell homeostasis and result in severe CNS pathologies. In this review, we discuss recent achievements that gave new insights into mechanisms that ensure microglia quiescence. PMID:23630462

  12. Risk Factors in Stroke

    PubMed Central

    Mustacchi, Piero

    1985-01-01

    In the United States, stroke accounts for 160,000 annual deaths; only 16% of the 1.8 million stroke survivors are fully independent. The incidence of stroke increases with age. Hemorrhagic strokes outnumber ischemic strokes before age 15. Japanese men in this country have a lower stroke mortality than their age peers in Japan. Excessive stroke mortality for US nonwhites may not be entirely due to the greater prevalence of hypertension among blacks. Hypertension emerges as the single most powerful and reversible risk factor in stroke and for survival after stroke. Impaired cardiac function is the second most important precursor of stroke. The recurrence of stroke in survivors is high. The frequency of completed stroke is high in persons with transient ischemic attacks, but not in those with asymptomatic carotid bruits. Other reversible risk factors are smoking, the use of oral contraceptives, alcoholic excess, a low level of physical activity, blood hyperviscosity and drug abuse. PMID:3898597

  13. Growth factors for nanobacteria

    NASA Astrophysics Data System (ADS)

    Ciftcioglu, Neva; Kajander, E. Olavi

    1999-12-01

    Nanobacteria are novel microorganisms recently isolated from fetal bovine serum and blood of cows and humans. These coccoid, gram negative bacteria in alpha-2 subgroup of Proteobacteria grow slowly under mammalian cell culture conditions but not in common media for microbes. Now we have found two different kinds of culture supplement preparations that improve their growth and make them culturable in the classical sense. These are supernatant fractions of conditioned media obtained from 1 - 3 months old nanobacteria cultures and from about a 2 weeks old Bacillus species culture. Both improved multiplication and particle yields and the latter increased their resistance to gentamicin. Nanobacteria cultured with any of the methods shared similar immunological property, structure and protein pattern. The growth supporting factors were heat-stabile and nondialyzable, and dialysis improved the growth promoting action. Nanobacteria formed stony colonies in a bacteriological medium supplemented with the growth factors. This is an implication that nanobacterial growth is influenced by pre-existing bacterial flora.

  14. Power Factor Controller

    NASA Technical Reports Server (NTRS)

    1997-01-01

    Frank Nola invented the Power Factor Controller (PFC) at Marshall Space Flight Center more than a decade ago. Nola came up with a way to curb power wastage in AC induction motors. The PFC matches voltage with the motor's actual need by continuously sensing shifts between voltage and current. When it senses a light load it cuts the voltage to the minimum needed. Potential energy savings range from 8 to 65 percent.

  15. Factorization of simulations

    SciTech Connect

    Barrett, C. L.; Mortveit, H. S.; Reidys, C. M.

    2001-01-01

    A simulation is collection of agents that, according to some schedule, are making decisions based on information about other agents in that collection. In this paper we present a class of dynamical systems called Sequential Dynamical Systems (SDS) that was developed to capture these key features of computer simulations. Here, as an example of the use of SDS, we demonstrate how one can obtain information about a simulation by a factorization into smaller simulations.

  16. Nucleon Electromagnetic Form Factors

    SciTech Connect

    Kees de Jager

    2004-08-01

    Although nucleons account for nearly all the visible mass in the universe, they have a complicated structure that is still incompletely understood. The first indication that nucleons have an internal structure, was the measurement of the proton magnetic moment by Frisch and Stern (1933) which revealed a large deviation from the value expected for a point-like Dirac particle. The investigation of the spatial structure of the nucleon, resulting in the first quantitative measurement of the proton charge radius, was initiated by the HEPL (Stanford) experiments in the 1950s, for which Hofstadter was awarded the 1961 Nobel prize. The first indication of a non-zero neutron charge distribution was obtained by scattering thermal neutrons off atomic electrons. The recent revival of its experimental study through the operational implementation of novel instrumentation has instigated a strong theoretical interest. Nucleon electro-magnetic form factors (EMFFs) are optimally studied through the exchange of a virtual photon, in elastic electron-nucleon scattering. The momentum transferred to the nucleon by the virtual photon can be selected to probe different scales of the nucleon, from integral properties such as the charge radius to scaling properties of its internal constituents. Polarization instrumentation, polarized beams and targets, and the measurement of the polarization of the recoiling nucleon have been essential in the accurate separation of the charge and magnetic form factors and in studies of the elusive neutron charge form factor.

  17. Fano factor estimation.

    PubMed

    Rajdl, Kamil; Lansky, Petr

    2014-02-01

    Fano factor is one of the most widely used measures of variability of spike trains. Its standard estimator is the ratio of sample variance to sample mean of spike counts observed in a time window and the quality of the estimator strongly depends on the length of the window. We investigate this dependence under the assumption that the spike train behaves as an equilibrium renewal process. It is shown what characteristics of the spike train have large effect on the estimator bias. Namely, the effect of refractory period is analytically evaluated. Next, we create an approximate asymptotic formula for the mean square error of the estimator, which can also be used to find minimum of the error in estimation from single spike trains. The accuracy of the Fano factor estimator is compared with the accuracy of the estimator based on the squared coefficient of variation. All the results are illustrated for spike trains with gamma and inverse Gaussian probability distributions of interspike intervals. Finally, we discuss possibilities of how to select a suitable observation window for the Fano factor estimation. PMID:24245675

  18. Human Factors Review Plan

    SciTech Connect

    Paramore, B.; Peterson, L.R.

    1985-12-01

    ''Human Factors'' is concerned with the incorporation of human user considerations into a system in order to maximize human reliability and reduce errors. This Review Plan is intended to assist in the assessment of human factors conditions in existing DOE facilities. In addition to specifying assessment methodologies, the plan describes techniques for improving conditions which are found to not adequately support reliable human performance. The following topics are addressed: (1) selection of areas for review describes techniques for needs assessment to assist in selecting and prioritizing areas for review; (2) human factors engineering review is concerned with optimizing the interfaces between people and equipment and people and their work environment; (3) procedures review evaluates completeness and accuracy of procedures, as well as their usability and management; (4) organizational interface review is concerned with communication and coordination between all levels of an organization; and (5) training review evaluates training program criteria such as those involving: trainee selection, qualification of training staff, content and conduct of training, requalification training, and program management.

  19. FACTORS INFLUENCING THE DESIGN OF BIOACCUMULATION FACTOR AND BIOTA-SEDIMENT ACCUMULATION FACTOR FIELD STUDIES

    EPA Science Inventory

    General guidance for designing field studies to measure bioaccumulation factors (BAFs) and biota-sediment accumulation factors (BSAFs) is not available. To develop such guidance, a series of modeling simulations were performed to evaluate the underlying factors and principles th...

  20. Risk Factors for Eating Disorders

    ERIC Educational Resources Information Center

    Striegel-Moore, Ruth H.; Bulik, Cynthia M.

    2007-01-01

    The authors review research on risk factors for eating disorders, restricting their focus to studies in which clear precedence of the hypothesized risk factor over onset of the disorder is established. They illustrate how studies of sociocultural risk factors and biological factors have progressed on parallel tracks and propose that major advances…

  1. Activation of human factor V by factor Xa and thrombin

    SciTech Connect

    Monkovic, D.D.; Tracy, P.B. )

    1990-02-06

    The activation of human factor V by factor Xa and thrombin was studied by functional assessment of cofactor activity and sodium dodecyl sulfate-polycarylamide gel electrophoresis followed by either autoradiography of {sup 125}I-labeled factor V activation products or Western blot analyses of unlabeled factor V activation products. Cofactor activity was measured by the ability of the factor V/Va peptides to support the activation of prothrombin. The factor Xa catalyzed cleavage of factor V was observed to be time, phospholipid, and calcium ion dependent, yielding a cofactor with activity equal to that of thrombin-activated factor V (factor Va). The cleavage pattern differed markedly from the one observed in the bovine system. The factor Xa activated factor V subunits expressing cofactor activity were isolated and found to consist of peptides of M{sub r} 220,000 and 105,000. Although thrombin cleaved the M{sub r} 220,000 peptide to yield peptides previously shown to be products of thrombin activation, cofactor activity did not increase. N-Terminal sequence analysis confirmed that both factor Xa and thrombin cleave factor V at the same bond to generate the M{sub r} 220,000 peptide. The factor Xa dependent functional assessment of {sup 125}I-labeled factor V coupled with densitometric analyses of the cleavage products indicated that the cofactor activity of factor Xa activated factor V closely paralleled the appearance of the M{sub r} 220,000 peptide. The data indicate that factor Xa is as efficient an enzyme toward factor V as thrombin.

  2. Milestones and Impact Factors

    PubMed Central

    2010-01-01

    Environmental Health has just received its first Impact Factor by Thomson ISI. At a level of 2.48, this achievement is quite satisfactory and places Environmental Health in the top 25% of environmental science journals. When the journal was launched in 2002, it was still unclear whether the Open Access publishing model could be made into a viable commercial enterprise within the biomedical field. During the past eight years, Open Access journals have become widely available, although still covering only about 15% of journal titles. Major funding agencies and institutions, including prominent US universities, now require that researchers publish in Open Access journals. Because of the profound role of scientific journals for the sharing of results and communication between researchers, the advent of Open Access may be of as much significance as the transition from handwriting to printing via moveable type. As Environmental Health is an electronic Open Access journal, the numbers of downloads at the journal website can be retrieved. The top-20 list of articles most frequently accessed shows that all of them have been downloaded over 10,000 times. Back in 2002, the first article published was accessed only 49 times during the following month. A year later, the server had over 1,000 downloads per month, and now the total number of monthly downloads approaches 50,000. These statistics complement the Impact Factor and confirm the viability of Open Access in our field of research. The advent of digital media and its decentralized mode of distribution - the internet - have dramatically changed the control and financing of scientific information dissemination, while facilitating peer review, accelerating editorial handling, and supporting much needed transparency. Both the meaning and means of "having an impact" are therefore changing, as will the degree and way in which scientific journals remain "factors" in that impact. PMID:20615249

  3. Neutron quality factor

    SciTech Connect

    1995-06-01

    Both the International Commission on Radiological Protection (ICRP) and the National Council on Radiation Protection and Measurements (NCRP) have recommended that the radiation quality weighting factor for neutrons (Q{sub n}, or the corresponding new modifying factor, w{sub R}) be increased by a value of two for most radiation protection practices. This means an increase in the recommended value for Q{sub n} from a nominal value of 10 to a nominal value of 20. This increase may be interpreted to mean that the biological effectiveness of neutrons is two times greater than previously thought. A decision to increase the value of Q{sub n} will have a major impact on the regulations and radiation protection programs of Federal agencies responsible for the protection of radiation workers. Therefore, the purposes of this report are: (1) to examine the general concept of {open_quotes}quality factor{close_quotes} (Q) in radiation protection and the rationale for the selection of specific values of Q{sub n}; and (2) to make such recommendations to the Federal agencies, as appropriate. This report is not intended to be an exhaustive review of the scientific literature on the biological effects of neutrons, with the aim of defending a particular value for Q{sub n}. Rather, the working group examined the technical issues surrounding the current recommendations of scientific advisory bodies on this matter, with the aim of determining if these recommendations should be adopted by the Federal agencies. Ultimately, the group concluded that there was no compelling basis for a change in Q{sub n}. The report was prepared by Federal scientists working under the auspices of the Science Panel of the Committee on Interagency Radiation Research and Policy Coordination (CIRRPC).

  4. Nucleon elastic form factors

    SciTech Connect

    D. Day

    2007-03-01

    The nucleon form factors are still the subject of active investigation even after an experimental effort spanning 50 years. This is because they are of critical importance to our understanding of the electromagnetic properties of nuclei and provide a unique testing ground for QCD motivated models of nucleon structure. Progress in polarized beams, polarized targets and recoil polarimetry have allowed an important and precise set of data to be collected over the last decade. I will review the experimental status of elastic electron scattering from the nucleon along with an outlook for future progress.

  5. Psychosocial factors in obesity.

    PubMed

    Mustajoki, P

    1987-01-01

    Obese people as a group have similar mental health as normal weight people, and there are no psychiatric features characteristic of obesity in general. However, small subgroups of obese individuals may have psychiatric abnormalities which are specific for obesity, such as body image disturbance or periodic compulsive overeating (bulimia). Obesity is strongly related to sociocultural factors. In western countries obesity is commoner in lower than in higher social classes. Thus, the development of obesity is influenced by social status. However, also the converse is true: recent observations suggest that obese people lose social status. This is probably due to prejudice and discrimination against obese persons in the modern western society. PMID:3477994

  6. Human Factors Model

    NASA Technical Reports Server (NTRS)

    1993-01-01

    Jack is an advanced human factors software package that provides a three dimensional model for predicting how a human will interact with a given system or environment. It can be used for a broad range of computer-aided design applications. Jack was developed by the computer Graphics Research Laboratory of the University of Pennsylvania with assistance from NASA's Johnson Space Center, Ames Research Center and the Army. It is the University's first commercial product. Jack is still used for academic purposes at the University of Pennsylvania. Commercial rights were given to Transom Technologies, Inc.

  7. Stress intensity factors

    SciTech Connect

    Erdogan, F.

    1983-12-01

    In this work the concept of the stress intensity factor, the underlying mechanics problem leading to its emergence, and its physical relevance, particularly its relation to fracture mechanics are discussed. The reasons as to why it has become nearly an indispensable tool for studying such important phenomena as brittle fracture and fatigue or corrosion fatigue crack propagation in structural solids are considered. A brief discussion of some of the important methods of solution of elastic crack problems is given. Also, a number of related special mechanics problems are described. 24 references.

  8. Electromagnetic pion form factor

    SciTech Connect

    Roberts, C.D.

    1995-08-01

    A phenomenological Dyson-Schwinger/Bethe-Salpeter equation approach to QCD, formalized in terms of a QCD-based model field theory, the Global Color-symmetry Model (GCM), was used to calculate the generalized impulse approximation contribution to the electromagnetic pion form factor at space-like q{sup 2} on the domain [0,10] GeV{sup 2}. In effective field theories this form factor is sometimes understood as simply being due to Vector Meson Dominance (VMD) but this does not allow for a simple connection with QCD where the VMD contribution is of higher order than that of the quark core. In the GCM the pion is treated as a composite bound state of a confined quark and antiquark interacting via the exchange of colored vector-bosons. A direct study of the quark core contribution is made, using a quark propagator that manifests the large space-like-q{sup 2} properties of QCD, parameterizes the infrared behavior and incorporates confinement. It is shown that the few parameters which characterize the infrared form of the quark propagator may be chosen so as to yield excellent agreement with the available data. In doing this one directly relates experimental observables to properties of QCD at small space-like-q{sup 2}. The incorporation of confinement eliminates endpoint and pinch singularities in the calculation of F{sub {pi}}(q{sup 2}). With asymptotic freedom manifest in the dressed quark propagator the calculation yields q{sup 4}F{sub {pi}}(q{sup 2}) = constant, up to [q{sup 2}]- corrections, for space-like-q{sup 2} {approx_gt} 35 GeV{sup 2}, which indicates that soft, nonperturbative contributions dominate the form factor at presently accessible q{sup 2}. This means that the often-used factorization Ansatz fails in this exclusive process. A paper describing this work was submitted for publication. In addition, these results formed the basis for an invited presentation at a workshop on chiral dynamics and will be published in the proceedings.

  9. From compatible factorization to near-compatible factorization

    NASA Astrophysics Data System (ADS)

    Aldiabat, Raja'i.; Ibrahim, Haslinda

    2014-12-01

    A compatible factorization of order ν, is an ν× ν-1/2 array in which the entries in row i form a near-one-factor with focus i, and the triples associated with the rows contain no repetitions. In this paper, we aim to amend this compatible factorization so that we can display ν(ν-1)/2 - 2ν/3 triples with the minimum repeated triples. Throughout this paper we propose a new type of factorization called near-compatible factorization. First, we present the compatible factorization towards developing a near-compatible factorization. Second, we discuss briefly the necessary and sufficient conditions for the existence of near-compatible factorization. Then, we exemplify the construction for case ν = 9 as a groundwork in developing near-compatible factorization.

  10. Leukemia inhibitory factor (LIF).

    PubMed

    Nicola, Nicos A; Babon, Jeffrey J

    2015-10-01

    Leukemia inhibitory factor (LIF) is the most pleiotropic member of the interleukin-6 family of cytokines. It utilises a receptor that consists of the LIF receptor β and gp130 and this receptor complex is also used by ciliary neurotrophic growth factor (CNTF), oncostatin M, cardiotrophin1 (CT1) and cardiotrophin-like cytokine (CLC). Despite common signal transduction mechanisms (JAK/STAT, MAPK and PI3K) LIF can have paradoxically opposite effects in different cell types including stimulating or inhibiting each of cell proliferation, differentiation and survival. While LIF can act on a wide range of cell types, LIF knockout mice have revealed that many of these actions are not apparent during ordinary development and that they may be the result of induced LIF expression during tissue damage or injury. Nevertheless LIF does appear to have non-redundant actions in maternal receptivity to blastocyst implantation, placental formation and in the development of the nervous system. LIF has also found practical use in the maintenance of self-renewal and totipotency of embryonic stem cells and induced pluripotent stem cells. PMID:26187859

  11. Auxin response factors.

    PubMed

    Chandler, John William

    2016-05-01

    Auxin signalling involves the activation or repression of gene expression by a class of auxin response factor (ARF) proteins that bind to auxin response elements in auxin-responsive gene promoters. The release of ARF repression in the presence of auxin by the degradation of their cognate auxin/indole-3-acetic acid repressors forms a paradigm of transcriptional response to auxin. However, this mechanism only applies to activating ARFs, and further layers of complexity of ARF function and regulation are being revealed, which partly reflect their highly modular domain structure. This review summarizes our knowledge concerning ARF binding site specificity, homodimer and heterodimer multimeric ARF association and cooperative function and how activator ARFs activate target genes via chromatin remodelling and evolutionary information derived from phylogenetic comparisons from ARFs from diverse species. ARFs are regulated in diverse ways, and their importance in non-auxin-regulated pathways is becoming evident. They are also embedded within higher-order transcription factor complexes that integrate signalling pathways from other hormones and in response to the environment. The ways in which new information concerning ARFs on many levels is causing a revision of existing paradigms of auxin response are discussed. PMID:26487015

  12. SARSCEST (human factors)

    NASA Technical Reports Server (NTRS)

    Parsons, H. Mcilvaine

    1988-01-01

    People interact with the processes and products of contemporary technology. Individuals are affected by these in various ways and individuals shape them. Such interactions come under the label 'human factors'. To expand the understanding of those to whom the term is relatively unfamiliar, its domain includes both an applied science and applications of knowledge. It means both research and development, with implications of research both for basic science and for development. It encompasses not only design and testing but also training and personnel requirements, even though some unwisely try to split these apart both by name and institutionally. The territory includes more than performance at work, though concentration on that aspect, epitomized in the derivation of the term ergonomics, has overshadowed human factors interest in interactions between technology and the home, health, safety, consumers, children and later life, the handicapped, sports and recreation education, and travel. Two aspects of technology considered most significant for work performance, systems and automation, and several approaches to these, are discussed.

  13. Factors in risk perception

    PubMed

    Sjoberg

    2000-02-01

    Risk perception is a phenomenon in search of an explanation. Several approaches are discussed in this paper. Technical risk estimates are sometimes a potent factor in accounting for perceived risk, but in many important applications it is not. Heuristics and biases, mainly availability, account for only a minor portion of risk perception, and media contents have not been clearly implicated in risk perception. The psychometric model is probably the leading contender in the field, but its explanatory value is only around 20% of the variance of raw data. Adding a factor of "unnatural risk" considerably improves the psychometric model. Cultural Theory, on the other hand, has not been able to explain more than 5-10% of the variance of perceived risk, and other value scales have similarly failed. A model is proposed in which attitude, risk sensitivity, and specific fear are used as explanatory variables; this model seems to explain well over 30-40% of the variance and is thus more promising than previous approaches. The model offers a different type of psychological explanation of risk perception, and it has many implications, e.g., a different approach to the relationship between attitude and perceived risk, as compared with the usual cognitive analysis of attitude. PMID:10795334

  14. Enhanced target factor analysis.

    PubMed

    Rostami, Akram; Abdollahi, Hamid; Maeder, Marcel

    2016-03-10

    Target testing or target factor analysis, TFA, is a well-established soft analysis method. TFA answers the question whether an independent target test vector measured at the same wavelengths as the collection of spectra in a data matrix can be excluded as the spectrum of one of the components in the system under investigation. Essentially, TFA cannot positively prove that a particular test spectrum is the true spectrum of one of the components, it can, only reject a spectrum. However, TFA will not reject, or in other words TFA will accept, many spectra which cannot be component spectra. Enhanced Target Factor Analysis, ETFA addresses the above problem. Compared with traditional TFA, ETFA results in a significantly narrower range of positive results, i.e. the chance of a false positive test result is dramatically reduced. ETFA is based on feasibility testing as described in Refs. [16-19]. The method has been tested and validated with computer generated and real data sets. PMID:26893084

  15. Human antigen-presenting cells respond differently to gut-derived probiotic bacteria but mediate similar strain-dependent NK and T cell activation.

    PubMed

    Fink, Lisbeth N; Zeuthen, Louise H; Ferlazzo, Guido; Frøkiaer, Hanne

    2007-12-01

    The intestinal microbiota is essential for homeostasis of the local and systemic immune system, and particularly strains of lactic acid bacteria and Escherichia coli have been shown to have balancing effects on inflammatory conditions such as allergy and inflammatory bowel disease. However, in vitro assessment of the immunomodulatory effects of distinct strains may depend strongly on the cell type used as a model. To select the most appropriate model for screening of beneficial bacteria in human cells, the response to strains of intestinal bacteria of three types of antigen-presenting cells (APC) was compared; blood myeloid dendritic cells (DC), monocyte-derived DC and monocytes, and the effector response of natural killer cells and naïve T cells was characterized. Maturation induced by gut-derived bacteria differed between APC, with blood DC and monocytes responding with the production of IL-6 and tumour necrosis factor-alpha to bacteria, which elicited mainly IL-10 in monocyte-derived DC. In contrast, comparable IFN-gamma production patterns were found in both natural killer cells and T cells induced by all bacteria-matured APC. An inhibitory effect of certain strains on this IFN-gamma production was also mediated by all types of APC. The most potent responses were induced by monocyte-derived DC, which thus constitute a sensitive screening model. PMID:17903206

  16. Neurotrophic factors and neurologic disease.

    PubMed Central

    Holtzman, D M; Mobley, W C

    1994-01-01

    Discovered only 40 years ago, nerve growth factor is the prototypic neurotrophic factor. By binding to specific receptors on certain neurons in the peripheral nervous system and brain, nerve growth factor acts to enhance their survival, differentiation, and maintenance. In recent years, many additional neurotrophic factors have been discovered; some are structurally related to nerve growth factor while others are distinct from it. The robust actions of neurotrophic factors have suggested their use in preventing or lessening the dysfunction and death of neurons in neurologic disorders. We review the progress in defining neurotrophic factors and their receptors and in characterizing their actions. We also discuss some of the uses of neurotrophic factors in animal models of disease. Finally, we discuss how neurotrophic factors could be implicated in the pathogenesis of neurologic disorders. Images PMID:7975562

  17. Human factors in aviation

    NASA Technical Reports Server (NTRS)

    Wiener, Earl L. (Editor); Nagel, David C. (Editor)

    1988-01-01

    The fundamental principles of human-factors (HF) analysis for aviation applications are examined in a collection of reviews by leading experts, with an emphasis on recent developments. The aim is to provide information and guidance to the aviation community outside the HF field itself. Topics addressed include the systems approach to HF, system safety considerations, the human senses in flight, information processing, aviation workloads, group interaction and crew performance, flight training and simulation, human error in aviation operations, and aircrew fatigue and circadian rhythms. Also discussed are pilot control; aviation displays; cockpit automation; HF aspects of software interfaces; the design and integration of cockpit-crew systems; and HF issues for airline pilots, general aviation, helicopters, and ATC.

  18. Perioperative allergy: risk factors.

    PubMed

    Caffarelli, C; Stringari, G; Pajno, G B; Peroni, D G; Franceschini, F; Dello Iacono, I; Bernardini, R

    2011-01-01

    Perioperative anaphylactic as well as anaphylactoid reactions can be elicited by drugs, diagnostic agents, antiseptics, disinfectants and latex. In some individuals, allergic reactions occur in the absence of any evident risk factor. Previous history of specific safe exposure to a product does not permit to exclude the risk of having a reaction. We have systematically reviewed characteristics in the patient's history or clinical parameters that affect the risk of developing reactions during anesthesia. Evidence shows that patients with previous unexplained reaction during anesthesia are at risk for perioperative allergic reactions. An allergic reaction to an agent is associated with previous reaction to a product that is related with the culprit agent. Multiple surgery procedures, professional exposure to latex and allergy to fruit are associated with an increased frequency of latex allergy. It has been shown that in some instances, allergic perioperative reactions may be more common in atopic patients and in females. PMID:22014923

  19. Pion form factor

    SciTech Connect

    Ryong Ji, C.; Pang, A.; Szczepaniak, A.

    1994-04-01

    It is pointed out that the correct criterion to define the legal PQCD contribution to the exclusive processes in the lightcone perturbative expansion should be based on the large off-shellness of the lightcone energy in the intermediate states. In the lightcone perturbative QCD calculation of the pion form factor, the authors find that the legal PQCD contribution defined by the lightcone energy cut saturates in the smaller Q{sup 2} region compared to that defined by the gluon four-momentum square cut. This is due to the contribution by the highly off-energy-shell gluons in the end point regions of the phase space, indicating that the gluon four-momentum-square cut may have cut too much to define the legal PQCD.

  20. Nucleon Electromagnetic Form Factors

    SciTech Connect

    Marc Vanderhaeghen; Charles Perdrisat; Vina Punjabi

    2007-10-01

    There has been much activity in the measurement of the elastic electromagnetic proton and neutron form factors in the last decade, and the quality of the data has greatly improved by performing double polarization experiments, in comparison with previous unpolarized data. Here we review the experimental data base in view of the new results for the proton, and neutron, obtained at JLab, MAMI, and MIT-Bates. The rapid evolution of phenomenological models triggered by these high-precision experiments will be discussed, including the recent progress in the determination of the valence quark generalized parton distributions of the nucleon, as well as the steady rate of improvements made in the lattice QCD calculations.

  1. Unity power factor converter

    NASA Technical Reports Server (NTRS)

    Wester, Gene W. (Inventor)

    1980-01-01

    A unity power factor converter capable of effecting either inversion (dc-to-dc) or rectification (ac-to-dc), and capable of providing bilateral power control from a DC source (or load) through an AC transmission line to a DC load (or source) for power flow in either direction, is comprised of comparators for comparing the AC current i with an AC signal i.sub.ref (or its phase inversion) derived from the AC ports to generate control signals to operate a switch control circuit for high speed switching to shape the AC current waveform to a sine waveform, and synchronize it in phase and frequency with the AC voltage at the AC ports, by selectively switching the connections to a series inductor as required to increase or decrease the current i.

  2. Psychosomatic factors in pruritus

    PubMed Central

    Tey, Hong Liang; Wallengren, Joanna; Yosipovitch, Gil

    2013-01-01

    Pruritus and psyche are intricately and reciprocally related, with psychophysiological evidence and psychopathological explanations helping us to understand their complex association. Their interaction may be conceptualized and classified into 3 groups: pruritic diseases with psychiatric sequelae, pruritic diseases aggravated by psychosocial factors, and psychiatric disorders causing pruritus. Management of chronic pruritus is directed at treating the underlying causes and adopting a multidisciplinary approach to address the dermatologic, somatosensory, cognitive, and emotional aspects. Pharmcotherapeutic agents that are useful for chronic pruritus with comorbid depression and/or anxiety comprise selective serotonin reuptake inhibitors, mirtazapine, tricyclic antidepressants (amitriptyline and doxepin), and anticonvulsants (gabapentin, pregabalin); the role of neurokinin receptor-1 antagonists awaits verification. Antipsychotics are required for treating itch and formication associated with schizophrenia and delusion of parasitosis (including Morgellons disease). PMID:23245971

  3. Psychosomatic factors in pruritus.

    PubMed

    Tey, Hong Liang; Wallengren, Joanna; Yosipovitch, Gil

    2013-01-01

    Pruritus and psyche are intricately and reciprocally related, with psychophysiological evidence and psychopathological explanations helping us to understand their complex association. Their interaction may be conceptualized and classified into 3 groups: pruritic diseases with psychiatric sequelae, pruritic diseases aggravated by psychosocial factors, and psychiatric disorders causing pruritus. Management of chronic pruritus is directed at treating the underlying causes and adopting a multidisciplinary approach to address the dermatologic, somatosensory, cognitive, and emotional aspects. Pharmcotherapeutic agents that are useful for chronic pruritus with comorbid depression and/or anxiety comprise selective serotonin reuptake inhibitors, mirtazapine, tricyclic antidepressants (amitriptyline and doxepin), and anticonvulsants (gabapentin, pregabalin); the role of neurokinin receptor-1 antagonists awaits verification. Antipsychotics are required for treating itch and formication associated with schizophrenia and delusion of parasitosis (including Morgellons disease). PMID:23245971

  4. Helicopter Human Factors

    NASA Technical Reports Server (NTRS)

    Hart, Sandra G.; Sridhar, Banavar (Technical Monitor)

    1995-01-01

    Even under optimal conditions, helicopter flight is a most demanding form of human-machine interaction, imposing continuous manual, visual, communications, and mental demands on pilots. It is made even more challenging by small margins for error created by the close proximity of terrain in NOE flight and missions flown at night and in low visibility. Although technology advances have satisfied some current and proposed requirements, hardware solutions alone are not sufficient to ensure acceptable system performance and pilot workload. However, human factors data needed to improve the design and use of helicopters lag behind advances in sensor, display, and control technology. Thus, it is difficult for designers to consider human capabilities and limitations when making design decisions. This results in costly accidents, design mistakes, unrealistic mission requirements, excessive training costs, and challenge human adaptability. NASA, in collaboration with DOD, industry, and academia, has initiated a program of research to develop scientific data bases and design principles to improve the pilot/vehicle interface, optimize training time and cost, and maintain pilot workload and system performance at an acceptable level. Work performed at Ames, and by other research laboratories, will be reviewed to summarize the most critical helicopter human factors problems and the results of research that has been performed to: (1) Quantify/model pilots use of visual cues for vehicle control; (2) Improve pilots' performance with helmet displays of thermal imagery and night vision goggles for situation awareness and vehicle control; (3) Model the processes by which pilots encode maps and compare them to the visual scene to develop perceptually and cognitively compatible electronic map formats; (4) Evaluate the use of spatially localized auditory displays for geographical orientation, target localization, radio frequency separation; (5) Develop and flight test control

  5. Factor Rotation and Standard Errors in Exploratory Factor Analysis

    ERIC Educational Resources Information Center

    Zhang, Guangjian; Preacher, Kristopher J.

    2015-01-01

    In this article, we report a surprising phenomenon: Oblique CF-varimax and oblique CF-quartimax rotation produced similar point estimates for rotated factor loadings and factor correlations but different standard error estimates in an empirical example. Influences of factor rotation on asymptotic standard errors are investigated using a numerical…

  6. Environmental factors and aggressive behavior

    SciTech Connect

    Anderson, A.C.

    1982-07-01

    This paper briefly reviews some of the research areas which indicate a correlation between environmental factors and initiation of aggressive behavior. Environmental factors including lunar influences, month of birth, climate and the effects of crowding and certain chemicals are discussed.

  7. Plasma factor XIII and platelet factor XIII in hyperlipaemia.

    PubMed

    Cucuianu, M P; Miloszewski, K; Porutiu, D; Losowsky, M S

    1976-12-31

    Plasma factor XIII activity measured by a quantitative assay was found to be significantly higher in hypertriglyceridaemic patients (type IV and combined hyperlipoproteinaemia), as compared to normolipaemic controls. No such elevation in plasma factor XIII activity was found in patients with type Ha hyperlipaemia. Plasma pseudocholinesterase was found to parallel the elevated factor XIII activity in hypertriglyceridaemic subjects. In contrast, platelet factor XIII activity was not raised in hyperlipaemic subjects, and plasma factor XIII was found to be normal in a normolipaemic subjects with thrombocythaemia. It was concluded that there is no significant contribution from platelets to plasma factor XIII activity, and that the observed increase in plasma factor XIII in hypertriglyceridaemia results from enhanced hepatic synthesis of the enzyme. PMID:1037152

  8. FACTOR FINDER CD-ROM

    EPA Science Inventory

    The Factor Finder CD-ROM is a user-friendly, searchable tool used to locate exposure factors and sociodemographic data for user-defined populations. Factor Finder improves the exposure assessors and risk assessors (etc.) ability to efficiently locate exposure-related informatio...

  9. Factor Analysis of Intern Effectiveness

    ERIC Educational Resources Information Center

    Womack, Sid T.; Hannah, Shellie Louise; Bell, Columbus David

    2012-01-01

    Four factors in teaching intern effectiveness, as measured by a Praxis III-similar instrument, were found among observational data of teaching interns during the 2010 spring semester. Those factors were lesson planning, teacher/student reflection, fairness & safe environment, and professionalism/efficacy. This factor analysis was as much of a…

  10. Phonological Awareness: Factors of Influence

    ERIC Educational Resources Information Center

    Frohlich, Linda Paulina; Petermann, Franz; Metz, Dorothee

    2013-01-01

    Early child development is influenced by various genetic and environmental factors. This study aims to identify factors that affect the phonological awareness of preschool and first grade children. Based on a sample of 330 German-speaking children (mean age = 6.2 years) the following domains were evaluated: Parent factors, birth and pregnancy,…

  11. Salivary Gland Cancer: Risk Factors

    MedlinePlus

    ... Factors Request Permissions Print to PDF Salivary Gland Cancer: Risk Factors Approved by the Cancer.Net Editorial Board , 08/ ... anything that increases a person’s chance of developing cancer. Although risk factors often influence the development of cancer, most do ...

  12. Quantification of Emission Factor Uncertainty

    EPA Science Inventory

    Emissions factors are important for estimating and characterizing emissions from sources of air pollution. There is no quantitative indication of uncertainty for these emission factors, most factors do not have an adequate data set to compute uncertainty, and it is very difficult...

  13. Risk Factor Assessment Branch (RFAB)

    Cancer.gov

    The Risk Factor Assessment Branch (RFAB) focuses on the development, evaluation, and dissemination of high-quality risk factor metrics, methods, tools, technologies, and resources for use across the cancer research continuum, and the assessment of cancer-related risk factors in the population.

  14. Factor Analysis via Components Analysis

    ERIC Educational Resources Information Center

    Bentler, Peter M.; de Leeuw, Jan

    2011-01-01

    When the factor analysis model holds, component loadings are linear combinations of factor loadings, and vice versa. This interrelation permits us to define new optimization criteria and estimation methods for exploratory factor analysis. Although this article is primarily conceptual in nature, an illustrative example and a small simulation show…

  15. [Environmental factors in ALS].

    PubMed

    Juntas-Morales, Raul; Pageot, Nicolas; Corcia, Philippe; Camu, William

    2014-05-01

    ALS is likely to be a disorder of multifactorial origin. Among all the factors that may increase the risk of ALS, environmental ones are being studied for many years, but in the recent years, several advances have pointed to a new interest in their potential involvement in the disease process, especially for the cyanotoxin BMAA. Food containing BMAA has been found on Guam, a well-known focus of ALS/parkinsonism/dementia and high levels of BMAA have been identified into the brain of these patients. The BMAA cyanotoxin is potentially ubiquitous and have also been found into the food of patients who died from ALS both in Europe and USA. BMAA can be wrongly integrated into the protein structure during mRNA traduction, competing with serine. This may induce abnormal protein folding and a subsequent cell death. Heavy metals, such as lead or mercury may be directly toxic for neuronal cells. Several works have suggested an increased risk of ALS in individuals chronically exposed to these metals. Exposure to pesticides has been suggested to be linked to an increased risk of developing ALS. The mechanism of their toxicity is likely to be mediated by paraoxonases. These proteins are in charge of detoxifying the organism from toxins, and particularly organophosphates. To date, there are insufficient scientific data to suggest that exposure to electromagnetic fields may increase the risk of having ALS. We are particularly missing longitudinal cohorts to demonstrate that risk. PMID:24703731

  16. Dietary factors and hyperuricaemia.

    PubMed

    Schlesinger, Naomi

    2005-01-01

    The connection of gout and hyperuricaemia with gluttony, overindulgence in food and alcohol and obesity dates from ancient times. Studies from different parts of the world suggest that the incidence and severity of hyperuricaemia and gout may be increasing. Uric acid (urate) is the end product of purine degradation. Although most uric acid is derived from the metabolism of endogenous purine, eating foods rich in purines contributes to the total pool of uric acid. Sustained hyperuricaemia is a risk factor for acute gouty arthritis, chronic tophaceous gout, renal stones and possibly cardiovascular events and mortality. Before starting lifelong urate-lowering drug therapy, it is important to identify and treat underlying disorders that may be contributing to hyperuricaemia. It is relevant to recognize the strong association of the insulin resistance syndrome (IRS) (abdominal obesity, dyslipidaemia, hypertension, raised serum insulin levels and glucose intolerance) with hyperuricaemia. Consumption of meat, seafood and alcoholic beverages in moderation and attention to food portion size is important. Moderation in the consumption of not only beer but also other forms of alcohol is essential. In the obese, controlled weight management has the potential to lower serum urate in a quantitatively similar way to relatively unpalatable "low purine" diets. Non-fat milk and low-fat yogurt have a variety of health benefits and dairy products may have clinically meaningful antihyperuricaemic effects. In addition, fruits, such as cherries and high intakes of vegetable protein diet may reduce serum urate levels. PMID:16375734

  17. Human Factors in Training

    NASA Technical Reports Server (NTRS)

    Barshi, Immanuel; Byrne, Vicky; Arsintescu, Lucia; Connell, Erin

    2010-01-01

    Future space missions will be significantly longer than current shuttle missions and new systems will be more complex than current systems. Increasing communication delays between crews and Earth-based support means that astronauts need to be prepared to handle the unexpected on their own. As crews become more autonomous, their potential span of control and required expertise must grow to match their autonomy. It is not possible to train for every eventuality ahead of time on the ground, or to maintain trained skills across long intervals of disuse. To adequately prepare NASA personnel for these challenges, new training approaches, methodologies, and tools are required. This research project aims at developing these training capabilities. By researching established training principles, examining future needs, and by using current practices in space flight training as test beds, both in Flight Controller and Crew Medical domains, this research project is mitigating program risks and generating templates and requirements to meet future training needs. Training efforts in Fiscal Year 09 (FY09) strongly focused on crew medical training, but also began exploring how Space Flight Resource Management training for Mission Operations Directorate (MOD) Flight Controllers could be integrated with systems training for optimal Mission Control Center (MCC) operations. The Training Task addresses Program risks that lie at the intersection of the following three risks identified by the Project: 1) Risk associated with poor task design; 2) Risk of error due to inadequate information; and 3) Risk associated with reduced safety and efficiency due to poor human factors design.

  18. Human Factors in Training

    NASA Technical Reports Server (NTRS)

    Barshi, Immanuel; Byme, Vicky; Arsintescu, Lucia

    2008-01-01

    Future space missions will be significantly longer than current Shuttle missions and new systems will be more complex than current systems. Increasing communication delays between crews and Earth-based support means that astronauts need to be prepared to handle the unexpected on their own. As crews become more autonomous, their potential span of control and required expertise must grow to match their autonomy. It is not possible to train for every eventuality ahead of time on the ground, or to maintain trained skills across long intervals of disuse. To adequately prepare NASA personnel for these challenges, new training approaches, methodologies, and tools are required. This research project aims at developing these training capabilities. Training efforts in FY07 strongly focused on crew medical training, but also began exploring how Space Flight Resource Management training for Mission Operations Directorate (MOD) Flight Controllers could be integrated with systems training for optimal Mission Control Center operations. Beginning in January 2008, the training research effort will include team training prototypes and tools. The Training Task addresses Program risks that lie at the intersection of the following three risks identified by the Project: 1) Risk associated with poor task design; 2) Risk of error due to inadequate information; 3) Risk associated with reduced safety and efficiency due to poor human factors design.

  19. Human Factors in Training

    NASA Technical Reports Server (NTRS)

    Barshi, Immanuel; Byrne, Vicky; Arsintescu, Lucia; Connell, Erin; Sandor, Aniko

    2009-01-01

    Future space missions will be significantly longer than current shuttle missions and new systems will be more complex than current systems. Increasing communication delays between crews and Earth-based support means that astronauts need to be prepared to handle the unexpected on their own. As crews become more autonomous, their potential span of control and required expertise must grow to match their autonomy. It is not possible to train for every eventuality ahead of time on the ground, or to maintain trained skills across long intervals of disuse. To adequately prepare NASA personnel for these challenges, new training approaches, methodologies, and tools are required. This research project aims at developing these training capabilities. By researching established training principles, examining future needs, and by using current practices in space flight training as test beds, both in Flight Controller and Crew Medical domains, this research project is mitigating program risks and generating templates and requirements to meet future training needs. Training efforts in Fiscal Year 08 (FY08) strongly focused on crew medical training, but also began exploring how Space Flight Resource Management training for Mission Operations Directorate (MOD) Flight Controllers could be integrated with systems training for optimal Mission Control Center (MCC) operations. The Training Task addresses Program risks that lie at the intersection of the following three risks identified by the Project: (1) Risk associated with poor task design (2) Risk of error due to inadequate information (3) Risk associated with reduced safety and efficiency due to poor human factors design

  20. Growth factors in ischemic stroke

    PubMed Central

    Lanfranconi, S; Locatelli, F; Corti, S; Candelise, L; Comi, G P; Baron, P L; Strazzer, S; Bresolin, N; Bersano, A

    2011-01-01

    Abstract Data from pre-clinical and clinical studies provide evidence that colony-stimulating factors (CSFs) and other growth factors (GFs) can improve stroke outcome by reducing stroke damage through their anti-apoptotic and anti-inflammatory effects, and by promoting angiogenesis and neurogenesis. This review provides a critical and up-to-date literature review on CSF use in stroke. We searched for experimental and clinical studies on haemopoietic GFs such as granulocyte CSF, erythropoietin, granulocyte-macrophage colony-stimulating factor, stem cell factor (SCF), vascular endothelial GF, stromal cell-derived factor-1α and SCF in ischemic stroke. We also considered studies on insulin-like growth factor-1 and neurotrophins. Despite promising results from animal models, the lack of data in human beings hampers efficacy assessments of GFs on stroke outcome. We provide a comprehensive and critical view of the present knowledge about GFs and stroke, and an overview of ongoing and future prospects. PMID:20015202

  1. Approximate factorization with source terms

    NASA Technical Reports Server (NTRS)

    Shih, T. I.-P.; Chyu, W. J.

    1991-01-01

    A comparative evaluation is made of three methodologies with a view to that which offers the best approximate factorization error. While two of these methods are found to lead to more efficient algorithms in cases where factors which do not contain source terms can be diagonalized, the third method used generates the lowest approximate factorization error. This method may be preferred when the norms of source terms are large, and transient solutions are of interest.

  2. Women's Career Success: A Factor Analytic Study of Contributing Factors.

    ERIC Educational Resources Information Center

    Gaskill, LuAnn Ricketts

    1991-01-01

    A survey of 466 women employed in retailing received 205 responses identifying (1) factors influencing the success and advancement of women in retailing and (2) how those factors differ for women in upper versus middle positions. Upper-level executives placed more importance on ambition and abilities; midlevel executives credited opportunity and…

  3. Five Describing Factors of Dyslexia.

    PubMed

    Tamboer, Peter; Vorst, Harrie C M; Oort, Frans J

    2016-09-01

    Two subtypes of dyslexia (phonological, visual) have been under debate in various studies. However, the number of symptoms of dyslexia described in the literature exceeds the number of subtypes, and underlying relations remain unclear. We investigated underlying cognitive features of dyslexia with exploratory and confirmatory factor analyses. A sample of 446 students (63 with dyslexia) completed a large test battery and a large questionnaire. Five factors were found in both the test battery and the questionnaire. These 10 factors loaded on 5 latent factors (spelling, phonology, short-term memory, rhyme/confusion, and whole-word processing/complexity), which explained 60% of total variance. Three analyses supported the validity of these factors. A confirmatory factor analysis fit with a solution of five factors (RMSEA = .03). Those with dyslexia differed from those without dyslexia on all factors. A combination of five factors provided reliable predictions of dyslexia and nondyslexia (accuracy >90%). We also looked for factorial deficits on an individual level to construct subtypes of dyslexia, but found varying profiles. We concluded that a multiple cognitive deficit model of dyslexia is supported, whereas the existence of subtypes remains unclear. We discussed the results in relation to advanced compensation strategies of students, measures of intelligence, and various correlations within groups of those with and without dyslexia. PMID:25398549

  4. Factorized molecular wave functions: Analysis of the nuclear factor

    SciTech Connect

    Lefebvre, R.

    2015-06-07

    The exact factorization of molecular wave functions leads to nuclear factors which should be nodeless functions. We reconsider the case of vibrational perturbations in a diatomic species, a situation usually treated by combining Born-Oppenheimer products. It was shown [R. Lefebvre, J. Chem. Phys. 142, 074106 (2015)] that it is possible to derive, from the solutions of coupled equations, the form of the factorized function. By increasing artificially the interstate coupling in the usual approach, the adiabatic regime can be reached, whereby the wave function can be reduced to a single product. The nuclear factor of this product is determined by the lowest of the two potentials obtained by diagonalization of the potential matrix. By comparison with the nuclear wave function of the factorized scheme, it is shown that by a simple rectification, an agreement is obtained between the modified nodeless function and that of the adiabatic scheme.

  5. [Host factors and viral factors in hepatitis C treatment].

    PubMed

    Sakamoto, Minoru; Enomoto, Nobuyuki

    2015-02-01

    In the interferon-based therapy for hepatitis C, host factors such as age, gender, liver fibrosis and steatosis are important as a therapeutic effect predictor, and viral factors such as HCV genotype, HCV viral load, HCV gene (IL28B, ITPA) are also important. In addition in genotype 1b, ISDR/IRRDR and core amino acid substitution are important. Also in the DAA treatment, viral factors are also important at the view of therapeutic effect and difficulty of acquisition of drug resistance mutation. In addition, the goal of treatment of hepatitis C are suppression of liver fibrosis progression and liver cancer and improvement of quality of life due to this (quality of life: QOL) and life prognosis, it is important to understand the host factors and HCV viral factors. PMID:25764672

  6. Factors That Influence Teacher Attrition.

    ERIC Educational Resources Information Center

    Gonzalez, Patricia

    1995-01-01

    External, employment, and personal factors which influence teacher decisions to stay, leave, or transfer from teaching assignments are discussed, with emphasis on special education teachers. Factors attributed to teacher attrition in urban and rural environments also are briefly reviewed, along with attrition of related services professionals.…

  7. Matrix factorizations and elliptic fibrations

    NASA Astrophysics Data System (ADS)

    Omer, Harun

    2016-09-01

    I use matrix factorizations to describe branes at simple singularities of elliptic fibrations. Each node of the corresponding Dynkin diagrams of the ADE-type singularities is associated with one indecomposable matrix factorization which can be deformed into one or more factorizations of lower rank. Branes with internal fluxes arise naturally as bound states of the indecomposable factorizations. Describing branes in such a way avoids the need to resolve singularities. This paper looks at gauge group breaking from E8 fibers down to SU (5) fibers due to the relevance of such fibrations for local F-theory GUT models. A purpose of this paper is to understand how the deformations of the singularity are understood in terms of its matrix factorizations. By systematically factorizing the elliptic fiber equation, this paper discusses geometries which are relevant for building semi-realistic local models. In the process it becomes evident that breaking patterns which are identical at the level of the Kodaira type of the fibers can be inequivalent at the level of matrix factorizations. Therefore the matrix factorization picture supplements information which the conventional less detailed descriptions lack.

  8. Risk Factors for Teenage Fatherhood.

    ERIC Educational Resources Information Center

    Thornberry, Terence P.; Smith, Carolyn A.; Howard, Gregory J.

    1997-01-01

    Uses data from the Rochester Youth Development Study of urban youth (N=615) to identify early risk factors for the likelihood of becoming a teen father. Results show that teen fatherhood is related to a variety of risk factors, such as social class, educational performance, precocious sexual activity, and drug use. (RJM)

  9. Stroke prevention: modifying risk factors

    PubMed Central

    Romero, José Rafael; Morris, Jane; Pikula, Aleksandra

    2009-01-01

    Risk factor modification remains as the principal aspect of care for stroke prevention. Understanding of risk factors has advanced and several options are now available to treat modifiable risk factors. However, effective treatment remains a challenging task in clinical practice. Prevention begins with awareness of risk factors by patients and clinicians. Risk factor assessment along with overall stroke risk estimation should be part of evaluation of patients with stroke, and used with careful clinical judgment. In this review we discuss the impact of modifiable traditional vascular risk factors on ischemic stroke, interventions for stroke prevention, and evidence for early treatment of risk factors where available as well as areas of research progress. Emphasis should be paid in education of patients, the community and medical personnel. Future research in the field of genetic determinants of vascular risk factors and stroke will increase our understanding of the underlying mechanisms of cerebrovascular disease and likely result in development of new therapies and individualized programs for stroke prevention. PMID:19124428

  10. About the Exposure Factors Program

    EPA Science Inventory

    The development of the latest version of the Exposure Factors Handbook (EFH): 2011 Edition (EPA/600/R-09/052F) has maintained the need for a more comprehensive program that addresses issues related to exposure factors. Since the first version of the EFH was r...

  11. Factorization with genus 2 curves

    NASA Astrophysics Data System (ADS)

    Cosset, Romain

    2010-04-01

    The elliptic curve method (ECM) is one of the best factorization methods available. It is possible to use hyperelliptic curves instead of elliptic curves but it is in theory slower. We use special hyperelliptic curves and Kummer surfaces to reduce the complexity of the algorithm. Our implementation GMP-HECM is faster than GMP-ECM for factoring large numbers.

  12. Statistical Factors in Complexation Reactions.

    ERIC Educational Resources Information Center

    Chung, Chung-Sun

    1985-01-01

    Four cases which illustrate statistical factors in complexation reactions (where two of the reactants are monodentate ligands) are presented. Included are tables showing statistical factors for the reactions of: (1) square-planar complexes; (2) tetrahedral complexes; and (3) octahedral complexes. (JN)

  13. Activity factors of the Korean exposure factors handbook.

    PubMed

    Jang, Jae-Yeon; Jo, Soo-Nam; Kim, So-Yeon; Lee, Kyung-Eun; Choi, Kyung-Ho; Kim, Young-Hee

    2014-01-01

    Exposure factors based on the Korean population are required for making appropriate risk assessment. It is expected that handbooks for exposure factors will be applied in many fields, as well as by health department risk assessors. The present article describes the development of an exposure factors handbook that specifically focuses on human activities in situations involving the possible risk of exposure to environmental contaminants. We define majour exposure factors that represent behavioral patterns for risk assessment, including time spent on routine activities, in different places, on using transportation, and engaged in activities related to water contact including swimming, bathing and washing. Duration of residence and employment are also defined. National survey data were used to identify recommended levels of exposure factors in terms of time spent on routine activities and period of residence and employment. An online survey was conducted with 2073 subjects who were selected using a stratified random sampling method in order to develop a list of exposure factors for the time spent in different places and in performing water-related activities. We provide the statistical distribution of the variables, and report reference levels of average exposure based on the reliable data in our exposure factors handbook. PMID:24570804

  14. Optimizing human factors in dentistry

    PubMed Central

    Gupta, Arpit; Ankola, Anil V.; Hebbal, Mamata

    2013-01-01

    Occupational health hazards among dental professionals are on a continuous rise and they have a significant negative overall impact on daily life. This review is intended to provide the information regarding risk factors and to highlight the prevention strategies for optimizing human factors in dentistry. Risk factors among dentists are multifactorial, which can be categorized into biomechanical and psychosocial. To achieve a realistic target of safety and health at work, prevention is clearly the best approach; therefore, musculoskeletal disorders can be reduced through proper positioning of dental worker and patient, regular rest breaks, general good health, using ergonomic equipment, and exercises designed to counteract the particular risk factors for the dental occupation. However, substantial evidences are still required to elucidate the potential risk factors and to formulate effective prevention programs. PMID:23946745

  15. Mitotic bookmarking by transcription factors

    PubMed Central

    2013-01-01

    Mitosis is accompanied by dramatic changes in chromatin organization and nuclear architecture. Transcription halts globally and most sequence-specific transcription factors and co-factors are ejected from mitotic chromatin. How then does the cell maintain its transcriptional identity throughout the cell division cycle? It has become clear that not all traces of active transcription and gene repression are erased within mitotic chromatin. Many histone modifications are stable or only partially diminished throughout mitosis. In addition, some sequence-specific DNA binding factors have emerged that remain bound to select sites within mitotic chromatin, raising the possibility that they function to transmit regulatory information through the transcriptionally silent mitotic phase, a concept that has been termed “mitotic bookmarking.” Here we review recent approaches to studying potential bookmarking factors with regards to their mitotic partitioning, and summarize emerging ideas concerning the in vivo functions of mitotically bound nuclear factors. PMID:23547918

  16. Factoring in Factor VIII With Acute Ischemic Stroke

    PubMed Central

    Siegler, James E.; Samai, Alyana; Albright, Karen C.; Boehme, Amelia K.; Martin-Schild, Sheryl

    2016-01-01

    There is growing research interest into the etiologies of cryptogenic stroke, in particular as it relates to hypercoagulable states. An elevation in serum levels of the procoagulant factor VIII is recognized as one such culprit of occult cerebral infarctions. It is the objective of the present review to summarize the molecular role of factor VIII in thrombogenesis and its clinical use in the diagnosis and prognosis of acute ischemic stroke. We also discuss the utility of screening for serum factor VIII levels among patients at risk for, or those who have experienced, ischemic stroke. PMID:25669199

  17. Inhibition of Hageman factor (factor XII) by popcorn inhibitor.

    PubMed

    Kambhu, S A; Ratnoff, O D; Everson, B

    1985-05-01

    A protein derived from sweet corn or popcorn inhibits the enzymatic activity of the carboxy-terminal fragment of Hageman factor (HFf) and of ellagic acid-activated Hageman factor (HF, factor XII). Not clarified is whether the inhibitor is directed at the active site of HF. Filtration of normal plasma or purified HF through columns of popcorn inhibitor bound to agarose gels demonstrated that HF was bound to these gels and could then be eluted by buffers containing 2.0 mol/L sodium chloride. The eluted HF was in the precursor form. Thus, popcorn inhibitor appeared to attach to a point on the carboxy-terminal HFf that was distinct from the enzymatically active site of this clotting factor. PMID:3989356

  18. Using Bayes factors for multi-factor, biometric authentication

    NASA Astrophysics Data System (ADS)

    Giffin, A.; Skufca, J. D.; Lao, P. A.

    2015-01-01

    Multi-factor/multi-modal authentication systems are becoming the de facto industry standard. Traditional methods typically use rates that are point estimates and lack a good measure of uncertainty. Additionally, multiple factors are typically fused together in an ad hoc manner. To be consistent, as well as to establish and make proper use of uncertainties, we use a Bayesian method that will update our estimates and uncertainties as new information presents itself. Our algorithm compares competing classes (such as genuine vs. imposter) using Bayes Factors (BF). The importance of this approach is that we not only accept or reject one model (class), but compare it to others to make a decision. We show using a Receiver Operating Characteristic (ROC) curve that using BF for determining class will always perform at least as well as the traditional combining of factors, such as a voting algorithm. As the uncertainty decreases, the BF result continues to exceed the traditional methods result.

  19. Development of stress intensification factors

    SciTech Connect

    Minichiello, J.C.; Rodabaugh, E.C.

    1995-12-01

    B31.1 Equation 13A, B31.3 Equation 18, and Section 3 Paragraphs NC/ND-3653 EQS. (10), (10a), and 11 all use i-factors (SIFs) to compute stresses in piping due to displacement induced loadings. Appendix D of the B31 Standards and Figure NC/ND-3673.2(b)-1 of Section 3 give values of i-factors for commonly used piping components. A need occasionally arises to establish i-factors for other components (e.g., a branch connection in an elbow). In order to provide guidance on the development of these factors, a new draft Appendix has been prepared to assure that the experimental procedures and interpretation of the test results leading to new i-factors are consistent with the basis for existing i-factors. This paper discusses the background to the proposed Appendix, using the Section 3 version as a model, and also provides the authors` opinions an the need for experimental verification (vs purely analytical computation) of i-factors. The Appendix proposed is to be part of Appendix 2 of Section 3.

  20. GATA Transcription Factors and Cancer

    PubMed Central

    Zheng, Rena; Blobel, Gerd A.

    2010-01-01

    It has been almost a quarter century since it was first appreciated that a class of oncogenes contained in rapidly transforming avian retroviruses encoded DNA-binding transcription factors. As with other oncogenes, genetic recombination with the viral genome led to their overexpression or functional alteration. In the years that followed, alterations of numerous transcription factors were shown to be causatively involved in various cancers in human patients and model organisms. Depending on their normal cellular functions, these factors were subsequently categorized as proto-oncogenes or tumor suppressor genes. This review focuses on the role of GATA transcription factors in carcinogenesis. GATA factors are zinc finger DNA binding proteins that control the development of diverse tissues by activating or repressing transcription. GATA factors thus coordinate cellular maturation with proliferation arrest and cell survival. Therefore, a role of this family of genes in human cancers is not surprising. Prominent examples include structural mutations in GATA1 that are found in almost all megakaryoblastic leukemias in patients with Down syndrome; loss of GATA3 expression in aggressive, dedifferentiated breast cancers; and silencing of GATA4 and GATA5 expression in colorectal and lung cancers. Here, we discuss possible mechanisms of carcinogenesis vis-à-vis the normal functions of GATA factors as they pertain to human patients and mouse models of cancer. PMID:21779441

  1. Risk Factors For Chronic Rhinosinusitis

    PubMed Central

    Min, Jin-Young; Tan, Bruce K.

    2015-01-01

    Purpose of review To review the recent literature on risk factors for chronic rhinosinusitis (CRS) with an emphasis on genetic, comorbid diseases and environmental factors associated with CRS. Through identifying potential risk factors for CRS, we glean insights into the underlying pathogenic mechanisms and essential for developing effective therapeutic strategies. Recent findings Recent findings demonstrate that genetics, comorbid medical conditions including airway diseases, gastroesophageal reflux disease, inflammatory and autoimmune diseases and various demographic and environmental factors are associated with having a CRS diagnosis. Limitations of current studies include, variable application of disease definitions, lack of prospective longitudinal studies and a disproportionate focus on tertiary care populations. Summary CRS has a broad spectrum of associations ranging from genetics to comorbid diseases and environmental factors. These predisposing factors provide valuable information for possible designing therapeutic and preventive interventions. However, to better understand whether these associations cause CRS, further studies are needed to independently replicate findings, establish temporal relationships between exposure and disease onset, evaluate the influence of exposure dose on disease severity, and to understand the biological effects of these risk factors in the context of CRS. PMID:25479315

  2. Corrosion effects on friction factors

    SciTech Connect

    Magleby, H.L.; Shaffer, S.J.

    1996-03-01

    This paper presents the results of NRC-sponsored material specimen tests that were performed to determine if corrosion increases the friction factors of sliding surfaces of motor-operated gate valves, which could require higher forces to close and open safety-related valves when subjected to their design basis differential pressures. Friction tests were performed with uncorroded specimens and specimens subjected to accelerated corrosion. Preliminary tests at ambient conditions showed that corrosion increased the friction factors, indicating the need for additional tests duplicating valve operating parameters at hot conditions. The additional tests showed friction factors of corroded specimens were 0.1 to 0.2 higher than for uncorroded specimens, and that the friction factors of the corroded specimens were not very dependent on contact stress or corrosion film thickness. The measured values of friction factors for the three corrosion films tested (simulating three operating times) were in the range of 0.3 to 0.4. The friction factor for even the shortest simulated operating time was essentially the same as the others, indicating that the friction factors appear to reach a plateau and that the plateau is reached quickly.

  3. Factors Affecting Medical Service Quality

    PubMed Central

    MOSADEGHRAD, Ali Mohammad

    2014-01-01

    Abstract Background A better understanding of factors influencing quality of medical service can pinpoint better strategies for quality assurance in medical services. This study aimed to identify factors affecting the quality of medical services provided by Iranian physicians. Methods Exploratory in-depth individual interviews were conducted with sixty-four physicians working in various medical institutions in Iran. Results Individual, organizational and environmental factors enhance or inhibit the quality of medical services. Quality of medical services depends on the personal factors of the physician and patient, and factors pertaining to the healthcare setting and the broader environment. Conclusion Differences in internal and external factors such as availability of resources, patient cooperation and collaboration among providers affect the quality of medical services and patient outcomes. Supportive leadership, proper planning, education and training and effective management of resources and processes improve the quality of medical services. This article contributes to healthcare theory and practice by developing a conceptual framework for understanding factors that influence medical services quality. PMID:26060745

  4. Sequence Factorization with Multiple References

    PubMed Central

    Wandelt, Sebastian; Leser, Ulf

    2015-01-01

    The success of high-throughput sequencing has lead to an increasing number of projects which sequence large populations of a species. Storage and analysis of sequence data is a key challenge in these projects, because of the sheer size of the datasets. Compression is one simple technology to deal with this challenge. Referential factorization and compression schemes, which store only the differences between input sequence and a reference sequence, gained lots of interest in this field. Highly-similar sequences, e.g., Human genomes, can be compressed with a compression ratio of 1,000:1 and more, up to two orders of magnitude better than with standard compression techniques. Recently, it was shown that the compression against multiple references from the same species can boost the compression ratio up to 4,000:1. However, a detailed analysis of using multiple references is lacking, e.g., for main memory consumption and optimality. In this paper, we describe one key technique for the referential compression against multiple references: The factorization of sequences. Based on the notion of an optimal factorization, we propose optimization heuristics and identify parameter settings which greatly influence 1) the size of the factorization, 2) the time for factorization, and 3) the required amount of main memory. We evaluate a total of 30 setups with a varying number of references on data from three different species. Our results show a wide range of factorization sizes (optimal to an overhead of up to 300%), factorization speed (0.01 MB/s to more than 600 MB/s), and main memory usage (few dozen MB to dozens of GB). Based on our evaluation, we identify the best configurations for common use cases. Our evaluation shows that multi-reference factorization is much better than single-reference factorization. PMID:26422374

  5. Self-assembling peptide for co-delivery of HIV-1 CD8+ T cells epitope and Toll-like receptor 7/8 agonists R848 to induce maturation of monocyte derived dendritic cell and augment polyfunctional cytotoxic T lymphocyte (CTL) response.

    PubMed

    Ding, Yong; Liu, Jun; Lu, Sheng; Igweze, Justice; Xu, Wen; Kuang, Da; Zealey, Chris; Liu, Daheng; Gregor, Alex; Bozorgzad, Ardalan; Zhang, Lei; Yue, Elizabeth; Mujib, Shariq; Ostrowski, Mario; Chen, P

    2016-08-28

    Peptide based vaccine that incorporates one or several highly conserved CD8+ T cells epitopes to induce potent cytotoxic T lymphocyte (CTL) response is desirable for some infectious diseases, such as HIV-1 (human immunodeficiency virus-1), and cancers. However, the CD8+ T cells epitope is often weakly immunogenic, and thus requires a specific adjuvant or delivery system to enhance the efficiency. Here we investigated the use of self-assembling peptide EAK16-II based platform to achieve the co-delivery of CD8+ T cells epitope and TLR7/8 agonists (R848 or R837) for augmenting DCs maturation and HIV-1 specific CTL response. HIV-1 CTL epitope SL9 was conjugated with EAK16-II to obtain SL9-EAK16-II, which further spontaneously co-assembled with R848 or R837 in aqueous solution, forming co-assembled nanofibers. Fluorescence spectra and calorimetrical titration revealed the interaction between SL9-EAK16-II assemblies and R848 or R837 via hydrogen bonding and hydrophobic interaction, with the binding affinity (dissociation constant Kd) of 0.62μM or 0.53μM, respectively. Ex vivo generated DCs from HIV-1+ patients pulsed with the SL9-EAK16-II/R848 nanofibers stimulated significantly more polyfunctional SL9 specific CTLs, compared to the DCs pulsed with SL9 alone or the mixture of SL9 and TLR agonist. Furthermore, the nanofibers elicited stronger SL9 specific CTL response in vaccinated mice. Our findings suggest the self-assembling peptide EAK16-II might be used as a new delivery system for peptide based vaccines. PMID:27297778

  6. Human Factors In Aircraft Automation

    NASA Technical Reports Server (NTRS)

    Billings, Charles

    1995-01-01

    Report presents survey of state of art in human factors in automation of aircraft operation. Presents examination of aircraft automation and effects on flight crews in relation to human error and aircraft accidents.

  7. Radiant-interchange Configuration Factors

    NASA Technical Reports Server (NTRS)

    Hamilton, D C :; Morgan, W R

    1952-01-01

    A study is presented of the geometric configuration factors required for computing radiant heat transfer between opaque surfaces separated by a nonabsorbing medium and various methods of determining the configuration factors are discussed. Configuration-factor solutions available in the literature have been checked and the more complicated equations are presented as families of curves. Cases for point, line, and finite-area sources are worked out over a wide range of geometric proportions. These cases include several new configurations involving rectangles, triangles, and cylinders of finite length which are integrated and tabulated. An analysis is presented, in which configuration factors are employed of the radiant heat transfer to the rotor blades of a typical gas turbine under different conditions of temperature and pressure. (author)

  8. Chemical Specific Adjustment Factors Workshop

    EPA Science Inventory

    The World Health Organization, through the International Programme on Chemical Safety (IPCS), has established guidance on the use of mechanistic data to replace default uncertainty factors for interspecies extrapolation and intraspecies variability in deriving risk values such as...

  9. Factorization-based texture segmentation

    DOE PAGESBeta

    Yuan, Jiangye; Wang, Deliang; Cheriyadat, Anil M.

    2015-06-17

    This study introduces a factorization-based approach that efficiently segments textured images. We use local spectral histograms as features, and construct an M × N feature matrix using M-dimensional feature vectors in an N-pixel image. Based on the observation that each feature can be approximated by a linear combination of several representative features, we factor the feature matrix into two matrices-one consisting of the representative features and the other containing the weights of representative features at each pixel used for linear combination. The factorization method is based on singular value decomposition and nonnegative matrix factorization. The method uses local spectral histogramsmore » to discriminate region appearances in a computationally efficient way and at the same time accurately localizes region boundaries. Finally, the experiments conducted on public segmentation data sets show the promise of this simple yet powerful approach.« less

  10. Factorization-based texture segmentation

    SciTech Connect

    Yuan, Jiangye; Wang, Deliang; Cheriyadat, Anil M.

    2015-06-17

    This study introduces a factorization-based approach that efficiently segments textured images. We use local spectral histograms as features, and construct an M × N feature matrix using M-dimensional feature vectors in an N-pixel image. Based on the observation that each feature can be approximated by a linear combination of several representative features, we factor the feature matrix into two matrices-one consisting of the representative features and the other containing the weights of representative features at each pixel used for linear combination. The factorization method is based on singular value decomposition and nonnegative matrix factorization. The method uses local spectral histograms to discriminate region appearances in a computationally efficient way and at the same time accurately localizes region boundaries. Finally, the experiments conducted on public segmentation data sets show the promise of this simple yet powerful approach.

  11. Formulas for Image Factor Scores

    ERIC Educational Resources Information Center

    Hakstian, A. Ralph

    1973-01-01

    Formulas are presented in this paper for computing scores associated with factors of G, the image covariance matrix, under three conditions. The subject of the paper is restricted to "pure" image analysis. (Author/NE)

  12. Stroke Risk Factors and Symptoms

    MedlinePlus

    ... effective if given quickly. Every minute counts! "Stroke Risk Factors and Symptoms", NINDS. June 1, 2008. Prepared by: Office of Communications and Public Liaison National Institute of Neurological Disorders ...

  13. Predisposition Factors in Anorexia Nervosa.

    ERIC Educational Resources Information Center

    Nagel, K. L.; Jones, Karen H.

    1992-01-01

    Reviews literature concerned with investigating psychiatric disturbances and genetic variables hypothesized as predisposing factors in etiology of anorexia nervosa. Gives particular emphasis to research which discusses association between anorexia nervosa and depression. Reviews psychopharmacological evidence and family genetics studies. Offers…

  14. Factors That Impair Wound Healing

    PubMed Central

    Anderson, Kristin; Hamm, Rose L.

    2014-01-01

    The body's response to tissue injury in a healthy individual is an intricate, sequential physiologic process that results in timely healing with full re-epithelialization, resolution of drainage, and return of function to the affected tissue. Chronic wounds, however, do not follow this sequence of events and can challenge the most experienced clinician if the underlying factors that are impairing wound healing are not identified. The purpose of this article is to present recent information about factors that impair wound healing with the underlying pathophysiological mechanism that interferes with the response to tissue injury. These factors include co-morbidities (diabetes, obesity, protein energy malnutrition), medications (steroids, non-steroidal anti-inflammatory drugs or NSAIDs, anti-rejection medications), oncology interventions (radiation, chemotherapy), and life style habits (smoking, alcohol abuse). Successful treatment of any chronic wound depends upon identification and management of the factors for each individual. PMID:26199879

  15. Environmental Factors Inducing Human Cancers

    PubMed Central

    Parsa, N

    2012-01-01

    Background An explosion of research has been done in discovering how human health is affected by environmental factors. I will discuss the impacts of environmental cancer causing factors and how they continue to cause multiple disruptions in cellular networking. Some risk factors may not cause cancer. Other factors initiate consecutive genetic mutations that would eventually alter the normal pathway of cellular proliferations and differentiation. Genetic mutations in four groups of genes; (Oncogenes, Tumor suppressor genes, Apoptosis genes and DNA repairing genes) play a vital role in altering the normal cell division. In recent years, molecular genetics have greatly increased our understanding of the basic mechanisms in cancer development and utilizing these molecular techniques for cancer screening, diagnosis, prognosis and therapies. Inhibition of carcinogenic exposures wherever possible should be the goal of cancer prevention programs to reduce exposures from all environmental carcinogens. PMID:23304670

  16. Hidden Risk Factors for Women

    MedlinePlus

    ... high cholesterol. “Those are the most common risk factors,” according to Steven J. Kittner, M.D., director of the Maryland Stroke Center at the University of Maryland School of Medicine in Baltimore. “But ...

  17. Factors influencing dust suppressant effectiveness

    SciTech Connect

    Copeland, C.R.; Eisele, T.C.; Chesney, D.J.; Kawatra, S.K.

    2008-11-15

    Water sprays are a common method used to reduce particulate matter (PM) emissions. Various factors such as wettability, surface area coverage, fine particle engulfment rates, interparticle adhesion forces, suppressant penetration and suppressant longevity have all been suggested as critical factors in achieving effective PM control. However, it has not been established which of these factors are the most important. Experimental work indicated that suppressant penetration is the most critical of these factors. The length of time after application that suppressants were effective was also improved by using hygroscopic reagents that retained moisture to prevent evaporation. Maximizing suppressant penetration and improving suppressant longevity led to an average 86% reduction in PM10 concentrations in laboratory dust tower tests.

  18. Genetic factors and systemic sclerosis.

    PubMed

    Murdaca, Giuseppe; Contatore, Miriam; Gulli, Rossella; Mandich, Paola; Puppo, Francesco

    2016-05-01

    Systemic sclerosis (SSc) is a rare connective tissue disease of unknown etiology characterized by chronic inflammation and fibrosis of the skin, vascular abnormalities, and variable involvement of organs including kidneys, gastrointestinal tract, heart, and lungs. SSc shows a complex etiology in which both environmental and genetic factors seem to influence the onset and outcome of the disease. We provide an extensive overview of the genetic factors and epigenetic modifications and what their knowledge has revealed in terms of etiopathogenesis of SSc. PMID:26826434

  19. Factors influencing dental decision making.

    PubMed

    Grembowski, D; Milgrom, P; Fiset, L

    1988-01-01

    In clinical decision making, dentists routinely choose between alternative treatments such as crown vs amalgam/composite buildup, root canal vs extraction, fixed bridge vs removable partial denture, and prophylaxis vs subgingival curettage or periodontal scaling. A number of technical and patient factors can influence dentists' choice of treatment in these situations; however, little is known about their relative importance. To address this issue, a list of technical (e.g., periodontal status and caries rate) and patient (e.g., cost and patient preference) factors possibly influencing choice of treatment was developed for each pair of services. Responding to a mail questionnaire, 156 general dentists in Washington State listed the top three factors influencing their choice of service in each pair. Results revealed that dentists took different factors into account in choosing among alternative treatments. Technical factors dominated over patient concerns; only about 33 percent of the dentists considered patient factors important in choosing alternative therapies. The latter group was less preventively oriented, were solo practitioners, worked longer hours, and had lower prices. Results suggest patients may have little influence on prescriptions of therapy among experienced general dentists. PMID:3045303

  20. Interstitial fibrosis and growth factors.

    PubMed Central

    Lasky, J A; Brody, A R

    2000-01-01

    Interstitial pulmonary fibrosis (IPF) is scarring of the lung caused by a variety of inhaled agents including mineral particles, organic dusts, and oxidant gases. The disease afflicts millions of individuals worldwide, and there are no effective therapeutic approaches. A major reason for this lack of useful treatments is that few of the molecular mechanisms of disease have been defined sufficiently to design appropriate targets for therapy. Our laboratory has focused on the molecular mechanisms through which three selected peptide growth factors could play a role in the development of IPF. Hundreds of growth factors and cytokines could be involved in the complex disease process. We are studying platelet-derived growth factor because it is the most potent mesenchymal cell mitogen yet described, transforming growth factor beta because it is a powerful inducer of extracellular matrix (scar tissue) components by mesenchymal cells, and tumor necrosis factor alpha because it is a pleiotropic cytokine that we and others have shown is essential for the development of IPF in animal models. This review describes some of the evidence from studies in humans, in animal models, and in vitro, that supports the growth factor hypothesis. The use of modern molecular and transgenic technologies could elucidate those targets that will allow effective therapeutic approaches. Images Figure 1 Figure 2 PMID:10931794

  1. Industrial Power Factor Analysis Guidebook.

    SciTech Connect

    Electrotek Concepts.

    1995-03-01

    Power factor is a way of measuring the percentage of reactive power in an electrical system. Reactive power represents wasted energy--electricity that does no useful work because the electrical current is out of phase with the voltage. Reactive power is used by inductive loads (such as, motors, transformers, fluorescent lights, arc welders and induction furnaces) to sustain their magnetic fields. Electric systems with many motors exhibit low power factors, increased conductor and transformer losses, and lower voltages. Utilities must supply both active and reactive power and compensate for these losses. Power factor can be improved by the addition of shunt capacitors. Capacitors act in opposition to inductive loads, thereby minimizing the reactive power required to serve them. In raising the power factor, shunt capacitors release energy to the system, reduce system losses, and ultimately decrease power costs. Improving system power factor can reduce reactive and active power losses for both industry and utilities through the addition of shunt capacitors. This Guide Book gives electric utility technical staff, industrial end-users, consultants and BPA employees a step-by-step method for evaluating the cost effectiveness of installing power factor correction capacitors in an industrial plant.

  2. Sexual harassment: identifying risk factors.

    PubMed

    O'Hare, E A; O'Donohue, W

    1998-12-01

    A new model of the etiology of sexual harassment, the four-factor model, is presented and compared with several models of sexual harassment including the biological model, the organizational model, the sociocultural model, and the sex role spillover model. A number of risk factors associated with sexually harassing behavior are examined within the framework of the four-factor model of sexual harassment. These include characteristics of the work environment (e.g., sexist attitudes among co-workers, unprofessional work environment, skewed sex ratios in the workplace, knowledge of grievance procedures for sexual harassment incidents) as well as personal characteristics of the subject (e.g., physical attractiveness, job status, sex-role). Subjects were 266 university female faculty, staff, and students who completed the Sexual Experience Questionnaire to assess the experience of sexual harassment and a questionnaire designed to assess the risk factors stated above. Results indicated that the four-factor model is a better predictor of sexual harassment than the alternative models. The risk factors most strongly associated with sexual harassment were an unprofessional environment in the workplace, sexist atmosphere, and lack of knowledge about the organization's formal grievance procedures. PMID:9883305

  3. Sparse Bayesian infinite factor models

    PubMed Central

    Bhattacharya, A.; Dunson, D. B.

    2011-01-01

    We focus on sparse modelling of high-dimensional covariance matrices using Bayesian latent factor models. We propose a multiplicative gamma process shrinkage prior on the factor loadings which allows introduction of infinitely many factors, with the loadings increasingly shrunk towards zero as the column index increases. We use our prior on a parameter-expanded loading matrix to avoid the order dependence typical in factor analysis models and develop an efficient Gibbs sampler that scales well as data dimensionality increases. The gain in efficiency is achieved by the joint conjugacy property of the proposed prior, which allows block updating of the loadings matrix. We propose an adaptive Gibbs sampler for automatically truncating the infinite loading matrix through selection of the number of important factors. Theoretical results are provided on the support of the prior and truncation approximation bounds. A fast algorithm is proposed to produce approximate Bayes estimates. Latent factor regression methods are developed for prediction and variable selection in applications with high-dimensional correlated predictors. Operating characteristics are assessed through simulation studies, and the approach is applied to predict survival times from gene expression data. PMID:23049129

  4. Factors influencing healthcare service quality

    PubMed Central

    Mosadeghrad, Ali Mohammad

    2014-01-01

    Background: The main purpose of this study was to identify factors that influence healthcare quality in the Iranian context. Methods: Exploratory in-depth individual and focus group interviews were conducted with 222 healthcare stakeholders including healthcare providers, managers, policy-makers, and payers to identify factors affecting the quality of healthcare services provided in Iranian healthcare organisations. Results: Quality in healthcare is a production of cooperation between the patient and the healthcare provider in a supportive environment. Personal factors of the provider and the patient, and factors pertaining to the healthcare organisation, healthcare system, and the broader environment affect healthcare service quality. Healthcare quality can be improved by supportive visionary leadership, proper planning, education and training, availability of resources, effective management of resources, employees and processes, and collaboration and cooperation among providers. Conclusion: This article contributes to healthcare theory and practice by developing a conceptual framework that provides policy-makers and managers a practical understanding of factors that affect healthcare service quality. PMID:25114946

  5. General factors of the Korean exposure factors handbook.

    PubMed

    Jang, Jae-Yeon; Kim, So-Yeon; Kim, Sun-Ja; Lee, Kyung-Eun; Cheong, Hae-Kwan; Kim, Eun-Hye; Choi, Kyung-Ho; Kim, Young-Hee

    2014-01-01

    Risk assessment considers the situations and characteristics of the exposure environment and host. Various physiological variables of the human body reflects the characteristics of the population that can directly influence risk exposure. Therefore, identification of exposure factors based on the Korean population is required for appropriate risk assessment. It is expected that a handbook about general exposure factors will be used by professionals in many fields as well as the risk assessors of the health department. The process of developing the exposure factors handbook for the Korean population will be introduced in this article, with a specific focus on the general exposure factors including life expectancy, body weight, surface area, inhalation rates, amount of water intake, and soil ingestion targeting the Korean population. The researchers used national databases including the Life Table and the 2005 Time Use Survey from the National Statistical Office. The anthropometric study of size in Korea used the resources provided by the Korean Agency for Technology and Standards. In addition, direct measurement and questionnaire surveys of representative samples were performed to calculate the inhalation rate, drinking water intake, and soil ingestion. PMID:24570802

  6. [Success factors in hospital management].

    PubMed

    Heberer, M

    1998-12-01

    The hospital environment of most Western countries is currently undergoing dramatic changes. Competition among hospitals is increasing, and economic issues have become decisive factors for the allocation of medical care. Hospitals therefore require management tools to respond to these changes adequately. The balanced scorecard is a method of enabling development and implementation of a business strategy that equally respects the financial requirements, the needs of the customers, process development, and organizational learning. This method was used to derive generally valid success factors for hospital management based on an analysis of an academic hospital in Switzerland. Strategic management, the focus of medical services, customer orientation, and integration of professional groups across the hospital value chain were identified as success factors for hospital management. PMID:10023551

  7. Environmental risk factors for osteoporosis

    SciTech Connect

    Goyer, R.A.; Korach, K.S. ); Epstein, S. ); Bhattacharyya, M. ); Pounds, J. )

    1994-04-01

    Environmental risk factors for osteoporosis were reviewed at a conference held at the National Institute for Environmental Health Sciences 8-9 November 1993. The conference was co-sponsored by the National Institute of Arthritis and Musculoskeletal and Skin Disease and the NIH Office of Research in Women's Health. The objective of the conference was to review what is known about risk factors for osteoporosis and to identify gaps in the present state of knowledge that might be addressed by future research. The conference was divided into two broad themes. The first session focused on current knowledge regarding etiology, risk factors, and approaches to clinical and laboratory diagnosis. This was followed by three sessions in which various environmental pollutants were discussed. Topics selected for review included environmental agents that interfere with bone and calcium metabolism, such as the toxic metals lead, cadmium, aluminum, and fluoride, natural and antiestrogens, calcium, and vitamin D.

  8. Success factors in technology development

    NASA Astrophysics Data System (ADS)

    Preston, John T.

    1995-01-01

    Universities in the U.S. have a significant impact on business through the transfer of technology. This paper describes goals and philosophy of the Technology Licensing Office at the Massachusetts Institute of Technology. This paper also relates the critical factors for susscessful technology transfer, particularly relating to new business formation. These critical factors include the quality of the technology, the quality of the management, the quality of the investor, the passion for success, and the image of the company. Descriptions of three different levels of investment are also given and the most successful level of investment for starting a new company is reviewed. Licensing to large companies is also briefly reviewed, as this type of licensing requires some different strategies than that of licensing to start-up companies. High quality critical factors and intelligent investment create rewards for the parties and successful ventures.

  9. Vascular growth factors in neuropsychiatry

    PubMed Central

    Newton, Samuel S.; Fournier, Neil M.; Duman, Ronald S.

    2014-01-01

    Recent advances in understanding the cellular and molecular basis of psychiatric illnesses have shed light on the important role played by trophic factors in modulating functional parameters associated with disease causality and drug action. Disease mechanisms are now thought to involve multiple cell types, including neurons and endothelial cells. These functionally distinct but interactively coupled cell types engage in cellular cross talk via shared and common signaling molecules. Dysregulation in their cellular signaling pathways influences brain function and alters behavioral performance. Multifunctional trophic factors such as VEGF and EPO that possess both neurotrophic and angiogenic actions are of particular interest due to their ability to rescue structural and plasticity deficits in neurons and vasculature. Obtaining insight into the behavioral, cellular and molecular actions of multi-functional trophic factors has the potential to open new and transformative therapeutic approaches. PMID:23475069

  10. Dnmt1/Transcription Factor Interactions

    PubMed Central

    Hervouet, Eric; Vallette, François M.; Cartron, Pierre-François

    2010-01-01

    DNA methylation inheritance is the process of copying, via the DNA methyltransferase 1 (Dnmt1), the pre-existing methylation patterns onto the new DNA strand during DNA replication. Experiments of chromatin immunoprecipitation, measurement of maintenance methyltransferase activity, proximity ligation in situ assays (P-LISA, Duolink/Olink), and transcription factor arrays demonstrate that Dnmt1 interacts with transcription factors to promote site-specific DNA methylation inheritance, while the Dnmt1-PCNA-UHRF1 complex promotes the DNA methylation inheritance without site preference. We also show that the Dnmt1-PCNA-UHRF1 and Dnmt1/transcription factor complexes methylate DNA by acting as a single player or in cooperation. Thus, our data establish that the copying of the pre-existing methylation pattern is governed by the orchestration of the untargeted and the targeted mechanisms of DNA methylation inheritance, which are themselves dictated by the partners of Dnmt1. PMID:21779454

  11. Isospectral potentials from modified factorization

    NASA Astrophysics Data System (ADS)

    Berger, Micheal S.; Ussembayev, Nail S.

    2010-08-01

    Factorization of quantum-mechanical potentials has a long history extending back to the earliest days of the subject. In the present article, the nonuniqueness of the factorization is exploited to derive new isospectral nonsingular potentials. Many one-parameter families of potentials can be generated from known potentials using a factorization that involves superpotentials defined in terms of excited states of a potential. For these cases an operator representation is available. If ladder operators are known for the original potential, then a straightforward procedure exists for defining such operators for its isospectral partners. The generality of the method is illustrated with a number of examples which may have many possible applications in atomic and molecular physics.

  12. Risk Factors in Adolescent Hypertension.

    PubMed

    Ewald, D Rose; Haldeman PhD, Lauren A

    2016-01-01

    Hypertension is a complex and multifaceted disease, with many contributing factors. While diet and nutrition are important influences, the confounding effects of overweight and obesity, metabolic and genetic factors, racial and ethnic predispositions, socioeconomic status, cultural influences, growth rate, and pubertal stage have even more influence and make diagnosis quite challenging. The prevalence of hypertension in adolescents far exceeds the numbers who have been diagnosed; studies have found that 75% or more go undiagnosed. This literature review summarizes the challenges of blood pressure classification in adolescents, discusses the impact of these confounding influences, and identifies actions that will improve diagnosis and treatment outcomes. PMID:27335997

  13. Risk Factors in Adolescent Hypertension

    PubMed Central

    Ewald, D. Rose; Haldeman, Lauren A.

    2016-01-01

    Hypertension is a complex and multifaceted disease, with many contributing factors. While diet and nutrition are important influences, the confounding effects of overweight and obesity, metabolic and genetic factors, racial and ethnic predispositions, socioeconomic status, cultural influences, growth rate, and pubertal stage have even more influence and make diagnosis quite challenging. The prevalence of hypertension in adolescents far exceeds the numbers who have been diagnosed; studies have found that 75% or more go undiagnosed. This literature review summarizes the challenges of blood pressure classification in adolescents, discusses the impact of these confounding influences, and identifies actions that will improve diagnosis and treatment outcomes. PMID:27335997

  14. Bayes factors and multimodel inference

    USGS Publications Warehouse

    Link, W.A.; Barker, R.J.

    2009-01-01

    Multimodel inference has two main themes: model selection, and model averaging. Model averaging is a means of making inference conditional on a model set, rather than on a selected model, allowing formal recognition of the uncertainty associated with model choice. The Bayesian paradigm provides a natural framework for model averaging, and provides a context for evaluation of the commonly used AIC weights. We review Bayesian multimodel inference, noting the importance of Bayes factors. Noting the sensitivity of Bayes factors to the choice of priors on parameters, we define and propose nonpreferential priors as offering a reasonable standard for objective multimodel inference.

  15. [Environmental Risk Factors for Dementia].

    PubMed

    Tashiro, Yoshitaka; Kinoshita, Ayae

    2016-07-01

    Owing to recent advancements in imaging techniques and biomarker research, the natural history of Alzheimer's disease (AD) has become clear from the very first preclinical stage. According to the study, more than 20 years before the onset of AD, Aβ starts to accumulate in the brain. This induces neurofibrillary tangle formation in the cerebral isocortex, leading to cognitive decline. If this process is suppressed, disease activity can be controlled. However, at this point, the best and most realistic way to deal with AD is to target the environmental factors that have been identified as risk factors by epidemiological studies. PMID:27395468

  16. Growth factors in orthopedic surgery

    PubMed Central

    Zaharia, C; Despa, N; Simionescu, M; Jinga, V; Fleseriu, I

    2010-01-01

    Growth factors have represented an essential issue of interest for the researchers and clinicians in orthopedics and trauma over the last 40 years. In the last 10 to 15 years, the advances registered in this field have permitted the identification of the most active cellular and humoral factors as well as the improvement of their use in the orthopedic and trauma surgery. Their domain of application has been continuously enlarged and the results have been visible from the beginning. The authors present their appreciation on the actual state of this subject as well as their experience with results and related conclusions. PMID:20302195

  17. Factors associated with caffeine consumption.

    PubMed

    Brice, Carolyn F; Smith, Andrew P

    2002-01-01

    The main aim of this research was to identify factors that were related to caffeine consumption. From this investigation it can be concluded that coffee is the main source of caffeine and that consumption varies with time of day. Individuals may be utilising the arousing effects of caffeine by consuming it at times when arousal is low for instance to counteract sleep inertia or a post-lunch dip in alertness. There is, however, very little evidence to suggest that psychological characteristics such as personality traits or psychosocial factors are important in influencing caffeine consumption, although smoking was found to be related to the amount of caffeine consumed. PMID:11820098

  18. Human factors and risk assessment

    SciTech Connect

    Al-Minhali, A.

    1996-11-01

    A case study was presented in the 1994 Abu Dhabi International Exhibition and Conference (ADIPEC, 94) which discussed the importance of investigating human factors in the design of a high integrity protection system (HIPS) to be installed on an offshore high pressure gas platform, (SPE reference ADSPE 80). This paper will follow up on the design changes, installation and operation of the HIPS with emphasis on practical implications as a result of improper integration of human factors in the system reliability and risk assessment studies.

  19. Prognostic factors in lupus nephritis.

    PubMed

    Mok, C C

    2005-01-01

    Systemic lupus erythematosus (SLE) is a heterogeneous disorder and its renal manifestations are protean. The course and prognosis of lupus nephritis is dependent on a large number of demographic, histopathological, serological, racial, socioeconomic and time dependent factors. Moreover, the initial and maintenance therapeutic regimens may also influence the long term renal outcome. This article reviews the important prognostic factors that have been reported in literature. The management strategy of lupus nephritis should be individualized and based on a composite of these parameters. PMID:15732286

  20. Environmental factors associated with asthma.

    PubMed Central

    Walker, Bailus; Stokes, Lynette D.; Warren, Rueben

    2003-01-01

    Asthma, a disease of attacks and remission, continues to account for substantial morbidity and direct economic costs. Numerous studies--epidemiologic, toxicologic and clinical--present evidence for a broad spectrum of environmental risk factors associated with asthma. This review summarizes current thinking on a subset of these factors. Knowledge of potential environmental determinants of asthma is important to both the patient and healthcare professional in the application of multiple modalities of medical and environmental intervention for management of the development, and exacerbation of this chronic inflammatory disorder of the airways. PMID:12760611

  1. Deregulated transcription factors in leukemia.

    PubMed

    Shima, Yutaka; Kitabayashi, Issay

    2011-08-01

    Specific chromosomal translocations and other mutations associated with acute myeloblastic leukemia (AML) often involve transcription factors and transcriptional coactivators. Such target genes include AML1, C/EBPα, RARα, MOZ, p300/CBP, and MLL, all of which are important in the regulation of hematopoiesis. The resultant fusion or mutant proteins deregulate the transcription of the affected genes and disrupt their essential role in hematopoiesis, causing differentiation block and abnormal proliferation and/or survival. This review focuses on such transcription factors and coactivators, and describes their roles in leukemogenesis and hematopoiesis. PMID:21823042

  2. Psychological factors in the antarctic.

    PubMed

    Rothblum, E D

    1990-05-01

    For the people who live and work in the Antarctic, isolation and extreme physical conditions cause considerable stress. This article reviews psychological research on Antarctic residents, focusing on factors related to the isolation (effective personnel selection, positive adjustment, conflict, and reintegration into the home environment) and factors related to the physical environment (the extreme cold, high altitude, increased radiation, sensory deprivation, and seasonal changes in activity level). Finally, Antarctic research has been applied to the study of future space travel and space station habitation. PMID:2189993

  3. Cortisol regulates the paracrine action of macrophages by inducing vasoactive gene expression in endometrial cells.

    PubMed

    Thiruchelvam, Uma; Maybin, Jacqueline A; Armstrong, Gregory M; Greaves, Erin; Saunders, Philippa T K; Critchley, Hilary O D

    2016-06-01

    The human endometrium undergoes inflammation and tissue repair during menstruation. We hypothesized that the local availability of bioactive glucocorticoids plays an important role in immune cell-vascular cell interactions in endometrium during tissue repair at menstruation, acting either directly or indirectly via tissue resident macrophages. We sought to determine whether endometrial macrophages are direct targets for glucocorticoids; whether cortisol-treated macrophages have a paracrine effect on angiogenic gene expression by endometrial endothelial cells; and whether endometrial macrophages express angiogenic factors. Human endometrium (n = 41) was collected with ethical approval and subject consent. Donor peripheral blood monocyte-derived macrophages were treated with estradiol, progesterone, or cortisol. The effect of peripheral blood monocyte-derived macrophage secretory products on the expression of angiogenic RNAs by endothelial cells was examined. Immunofluorescence was used to examine localization in macrophages and other endometrial cell types across the menstrual cycle. Endometrial macrophages express the glucocorticoid receptor. In vitro culture with supernatants from cortisol-treated peripheral blood monocyte-derived macrophages resulted in altered endometrial endothelial cell expression of the angiogenic genes, CXCL2, CXCL8, CTGF, and VEGFC These data highlight the importance of local cortisol in regulating paracrine actions of macrophages in the endometrium. CXCL2 and CXCL8 were detected in endometrial macrophages in situ. The expression of these factors was highest in the endometrium during the menstrual phase, consistent with these factors having a role in endometrial repair. Our data have indicated that activation of macrophages with glucocorticoids might have paracrine effects by increasing angiogenic factor expression by endometrial endothelial cells. This might reflect possible roles for macrophages in endometrial repair of the vascular bed

  4. Regulation of fibrinogen synthesis by plasmin-derived fragments of fibrinogen and fibrin: an indirect feedback pathway.

    PubMed Central

    Ritchie, D G; Levy, B A; Adams, M A; Fuller, G M

    1982-01-01

    The effect of plasmin-derived fibrinogen fragments on the biosynthesis of fibrinogen was investigated in cultured monolayers of rat hepatocytes. Incubating the cells with several concentrations of either fibrinogen or fibrin fragment D or E had no effect on the synthesis and secretion of fibrinogen by these cells. However, if the fragments were incubated with isolated peripheral blood leukocytes, they caused these cells to secrete a factor that when added to the hepatocytes caused an increase in fibrinogen synthesis 4- to 6-fold over controls. Moreover, the hepatocyte-stimulating factor also affected the production of several other proteins produced by the hepatocyte. These results demonstrate that both fragments D and E can stimulate hepatic fibrinogen synthesis via an indirect leukocyte-mediated pathway. Images PMID:6461860

  5. Synthetic Division and Matrix Factorization

    ERIC Educational Resources Information Center

    Barabe, Samuel; Dubeau, Franc

    2007-01-01

    Synthetic division is viewed as a change of basis for polynomials written under the Newton form. Then, the transition matrices obtained from a sequence of changes of basis are used to factorize the inverse of a bidiagonal matrix or a block bidiagonal matrix.

  6. Neurophysiological Factors in Spatial Development.

    ERIC Educational Resources Information Center

    Harris, Lauren Jay

    Some of the major lines of investigation that point to neurophysiological factors in spatial skill are presented. These lines include: the two hemispheres of the brain, recent studies, tachistoscopic studies, morphological differences between the cerebral hemispheres, Geschwind and Levitsky's discovery, cerebral dominance re-examined, sex…

  7. Employability Development Teams: Cohesion Factors

    ERIC Educational Resources Information Center

    Johnson, Douglas W.; Munger, Paul F.

    1972-01-01

    In this study the researchers attempted to analyze the factors of age, sex, racial-ethnic background, operational life of the team, educational status, leader status, team size, caseload size, and the location of program site in terms of their potential effects upon team cohesion. (Author)

  8. Time dependent view factor methods

    SciTech Connect

    Kirkpatrick, R.C.

    1998-03-01

    View factors have been used for treating radiation transport between opaque surfaces bounding a transparent medium for several decades. However, in recent years they have been applied to problems involving intense bursts of radiation in enclosed volumes such as in the laser fusion hohlraums. In these problems, several aspects require treatment of time dependence.

  9. On Techniques of Prime Factorization

    ERIC Educational Resources Information Center

    Cohen, David B.

    1977-01-01

    This article gives two methods of resolving natural numbers into prime factors. Depending upon the number that is being resolved, one method may be better to use than the other. However, it is difficult to tell beforehand which is the better method to employ. Examples are given. (Author/MA)

  10. Factors Affecting the Tutoring Process.

    ERIC Educational Resources Information Center

    Hartman, Hope J.

    1990-01-01

    Analyzes factors internal to the tutor and tutee (i.e., cognition, metacognition, and affect) and external to them (e.g., teacher/tutor background knowledge, educational environment, content to be learned, socioeconomic status, family background, and cultural forces) that influence the tutoring process. Suggests a theoretical framework for…

  11. Factors Influencing College Science Success

    ERIC Educational Resources Information Center

    Tai, Robert H.; Sadler, Philip M.; Mintzes, Joel J.

    2006-01-01

    In this paper, the authors report some of the salient findings of a large-scale, four-year national study, conducted at the Harvard-Smithsonian Center for Astrophysics, entitled "Factors Influencing College Science Success" (FICSS), which surveyed college students who enrolled in first-year biology, chemistry, and physics courses throughout the…

  12. Heredity Factors in Spatial Visualization.

    ERIC Educational Resources Information Center

    Vandenberg, S. G.

    Spatial visualization is not yet clearly understood. Some researchers have concluded that two factors or abilities are involved, spatial orientation and spatial visualization. Different definitions and different tests have been proposed for these two abilities. Several studies indicate that women generally perform more poorly on spatial tests than…

  13. [Psoriasis and cardiovascular risk factors].

    PubMed

    Tal, Roy; Pavlovsky, Lev; David, Michael

    2012-10-01

    Psoriasis is a common inflammatory skin disease which may dramatically affect patients' lives. This chronic disease is characterized by a protracted course of alternating remissions and relapses. In recent years, the attention of researchers has focused on the association between psoriasis and cardiovascular disease risk factors. This review summarizes the literature on this topic with an emphasis on research conducted in Israel. PMID:23316664

  14. Entropy algebras and Birkhoff factorization

    NASA Astrophysics Data System (ADS)

    Marcolli, Matilde; Tedeschi, Nicolas

    2015-11-01

    We develop notions of Rota-Baxter structures and associated Birkhoff factorizations, in the context of min-plus semirings and their thermodynamic deformations, including deformations arising from quantum information measures such as the von Neumann entropy. We consider examples related to Manin's renormalization and computation program, to Markov random fields and to counting functions and zeta functions of algebraic varieties.

  15. R factors from Serratia marcescens.

    PubMed

    Hedges, R W; Rodriguez-Lemoine, V; Datta, N

    1975-01-01

    In recent years, Serratia marcescens has become established in certain localities as an agent of hospital infection and cross-infection (Clayton & von Graevenitz, 1966; Wilfert, Barrett & Kass, 1968; Davis, Foltz & Blakemore, 1970; Wilkowske, Washington, Martin & Ritts, 1970). In general, strains of S. marcescens isolated from infective lesions differ from those from other sources in being non-pigmented and antibiotic resistant (Ewing, Johnson & David, 1962; Clayton & von Graevenitz, 1966). Medeiros & O'Brien (1969) and Schaefler et al. (1971) described strains of S. marcescens, isolated from hospital patients, which were able to transfer R factors to Escherichia coli. Transfer of resistance to E. coli has also been reported from strains of S. marcescens isolated in France (Grimont & Dulong de Rosnay, 1972; Scavizzi, 1972; Lemosquet-Villemon, Morel & Freymuth, 1973)9 We have collected strains of S. marcescens, most, but not all, clinical isolates, from widely separate geographical areas; each strain was tested for antibiotic resistance and for R factors transmissible to E. coli K129 The R factors were classified by compatibility in K12 (Datta, 1974). Our purpose was to find out how much of the antibiotic resistance observed in S. marcescens is characteristic of that genus and to what extent it is shared with other bacterial genera (Coetzee, Datta & Hedges, 1972; Datta & Hedges, 1972a; Hedges, 1974). The R factors described by Medeiros & O'Brien (1969) and Lemosquet-Villemon et al. (1973) were included in this study. PMID:1089756

  16. Stress Factors among College Educators.

    ERIC Educational Resources Information Center

    Grant, George Farid

    Stress factors affecting community college educators in Ontario were determined using a questionnaire survey. The effect of demographic variables (campus location, program types and specialization, gender, age, and years taught at the college) on perceived stress levels were evaluated. Participants rated their present stress levels on a…

  17. 2012 Critical Success Factors Report

    ERIC Educational Resources Information Center

    North Carolina Community College System (NJ1), 2012

    2012-01-01

    The Critical Success Factors Report is the North Carolina Community College System's major accountability document. This annual performance report is based on data compiled from the previous year and serves to inform colleges and the public on the performance of North Carolina's 58 community colleges. In 1993, the State Board of Community Colleges…

  18. 2011 Critical Success Factors Report

    ERIC Educational Resources Information Center

    North Carolina Community College System (NJ1), 2011

    2011-01-01

    The Critical Success Factors Report is the North Carolina Community College System's major accountability document. This annual performance report serves to inform colleges and the public on the performance of North Carolina's 58 community colleges. In 1993, the State Board of Community Colleges began monitoring performance data on specific…

  19. Human factors in underwater systems.

    PubMed

    Crosson, D

    1993-10-01

    Applications of human factors to undersea engineering and the relationship to aerospace science are explored. Cooperative ventures include the TEKTITE underwater habitat and development of better procedures to prevent decompression sickness. Other research involved the use of alternate gases in diving systems, remote-operation vehicles, and diving system tests. PMID:11541030

  20. Inner City Human Factors Evaluation.

    ERIC Educational Resources Information Center

    Griffith, Albert R.

    This evaluation examines the degree to which human factors support, relate to, or impede the successful achievements of Polaroid's Inner City mission to provide on-the-job training for the career development of disadvantaged workers. The program is cited as a model for industry-based career education. Background information is provided on the…

  1. Transcription factor-based biosensor

    SciTech Connect

    Dietrich, Jeffrey A; Keasling, Jay D

    2013-10-08

    The present invention provides for a system comprising a BmoR transcription factor, a .sigma..sup.54-RNA polymerase, and a pBMO promoter operatively linked to a reporter gene, wherein the pBMO promoter is capable of expression of the reporter gene with an activated form of the BmoR and the .sigma..sup.54-RNA polymerase.

  2. Soft Factors Influence College Enrollment

    ERIC Educational Resources Information Center

    Fogg, Neeta P.; Harrington, Paul E.

    2010-01-01

    Evidence about the role that "soft factors" like student engagement and school environment play in influencing whether high school students go on to enroll in college is hard to come by. Over the past two years, the Center for Labor Market Studies (CLMS) of Northeastern University, with support from the Nellie Mae Education Foundation and the…

  3. Highly parallel sparse Cholesky factorization

    NASA Technical Reports Server (NTRS)

    Gilbert, John R.; Schreiber, Robert

    1990-01-01

    Several fine grained parallel algorithms were developed and compared to compute the Cholesky factorization of a sparse matrix. The experimental implementations are on the Connection Machine, a distributed memory SIMD machine whose programming model conceptually supplies one processor per data element. In contrast to special purpose algorithms in which the matrix structure conforms to the connection structure of the machine, the focus is on matrices with arbitrary sparsity structure. The most promising algorithm is one whose inner loop performs several dense factorizations simultaneously on a 2-D grid of processors. Virtually any massively parallel dense factorization algorithm can be used as the key subroutine. The sparse code attains execution rates comparable to those of the dense subroutine. Although at present architectural limitations prevent the dense factorization from realizing its potential efficiency, it is concluded that a regular data parallel architecture can be used efficiently to solve arbitrarily structured sparse problems. A performance model is also presented and it is used to analyze the algorithms.

  4. Cognitive Factors in Academic Achievement.

    ERIC Educational Resources Information Center

    Cuasay, Peter

    1992-01-01

    This review explores the factors of cognitive processing, style, and metacognitive organization as they contribute to academic success. Specific discussions consider aspects of short- and long-term memory, including how these affect learning and academic performance, and the keys to attaining long-term memory capability by involving redundancy,…

  5. Risk factors for postoperative ileus

    PubMed Central

    Kutun, Suat; Ulucanlar, Haluk; Tarcan, Oguz; Demir, Abdullah; Cetin, Abdullah

    2011-01-01

    Purpose This study aimed to examine extended postoperative ileus and its risk factors in patients who have undergone abdominal surgery, and discuss the techniques of prevention and management thereof the light of related risk factors connected with our study. Methods This prospective study involved 103 patients who had undergone abdominal surgery. The effects of age, gender, diagnosis, surgical operation conducted, excessive small intestine manipulation, opioid analgesic usage time, and systemic inflammation on the time required for the restoration of intestinal motility were investigated. The parameters were investigated prospectively. Results Regarding the factors that affected the restoration of gastrointestinal motility, resection operation type, longer operation period, longer opioid analgesics use period, longer nasogastric catheter use period, and the presence of systemic inflammation were shown to retard bowel motility for 3 days or more. Conclusion Our study confirmed that unnecessary analgesics use in patients with pain tolerance with non-steroid anti-inflammatory drugs, excessive small bowel manipulation, prolonged nasogastric catheter use have a direct negative effect on gastrointestinal motility. Considering that an exact treatment for postoperative ileus has not yet been established, and in light of the risk factors mentioned above, we regard that prevention of postoperative ileus is the most effective way of coping with intestinal dysmotility. PMID:22111079

  6. Efficient networks for quantum factoring

    SciTech Connect

    Beckman, D.; Chari, A.N.; Devabhaktuni, S.; Preskill, J.

    1996-08-01

    We consider how to optimize memory use and computation time in operating a quantum computer. In particular, we estimate the number of memory quantum bits (qubits) and the number of operations required to perform factorization, using the algorithm suggested by Shor [in {ital Proceedings} {ital of} {ital the} 35{ital th} {ital Annual} {ital Symposium} {ital on} {ital Foundations} {ital of} {ital Computer} {ital Science}, edited by S. Goldwasser (IEEE Computer Society, Los Alamitos, CA, 1994), p. 124]. A {ital K}-bit number can be factored in time of order {ital K}{sup 3} using a machine capable of storing 5{ital K}+1 qubits. Evaluation of the modular exponential function (the bottleneck of Shor{close_quote}s algorithm) could be achieved with about 72{ital K}{sup 3} elementary quantum gates; implementation using a linear ion trap would require about 396{ital K}{sup 3} laser pulses. A proof-of-principle demonstration of quantum factoring (factorization of 15) could be performed with only 6 trapped ions and 38 laser pulses. Though the ion trap may never be a useful computer, it will be a powerful device for exploring experimentally the properties of entangled quantum states. {copyright} {ital 1996 The American Physical Society.}

  7. NASA Space Human Factors Program

    NASA Technical Reports Server (NTRS)

    1992-01-01

    This booklet briefly and succinctly treats 23 topics of particular interest to the NASA Space Human Factors Program. Most articles are by different authors who are mainly NASA Johnson or NASA Ames personnel. Representative topics covered include mental workload and performance in space, light effects on Circadian rhythms, human sleep, human reasoning, microgravity effects and automation and crew performance.

  8. The Environmental Factors Influencing Attrition.

    ERIC Educational Resources Information Center

    Villella, Edward F.

    1986-01-01

    Offers an economics/business-management perspective on student attrition, focusing on the external macro-environment (including such factors as government funding of education, changing enrollment patterns, and the increased number of postsecondary institutions) and the internal micro-environment (exhibiting characteristics of intangibility,…

  9. HUMAN PROSTATE CANCER RISK FACTORS

    EPA Science Inventory

    Prostate cancer has the highest prevalence of any non-skin cancer in the human body, with similar likelihood of neoplastic foci found within the prostates of men around the world regardless of diet, occupation, lifestyle, or other factors. Essentially all men with circulating an...

  10. Transforming Rubrics Using Factor Analysis

    ERIC Educational Resources Information Center

    Baryla, Ed; Shelley, Gary; Trainor, William

    2012-01-01

    Student learning and program effectiveness is often assessed using rubrics. While much time and effort may go into their creation, it is equally important to assess how effective and efficient the rubrics actually are in terms of measuring competencies over a number of criteria. This study demonstrates the use of common factor analysis to identify…

  11. Nutritional factors in human cancers.

    PubMed

    Giovannucci, E

    1999-01-01

    A variety of external factors interacting with genetic susceptibility influence the carcinogenesis process. External factors including oxidative compounds, electrophilic agents, and chronic infections may enhance genetic damage. In addition, various hormonal factors which influence growth and differentiation are critically important in the carcinogenic process. Diet and nutrition can influence these processes directly in the gastrointestinal tract by providing bioactive compounds to specific tissues via the circulatory system, or by modulating hormone levels. Differences in certain dietary patterns among populations explain a substantial proportion of cancers of the colon, prostate and breast. These malignancies are largely influenced by a combination of factors related to diet and nutrition. Their causes are multifactorial and complex, but a major influence is the widespread availability of energy-dense, highly processed and refined foods that are also deplete in fiber. These dietary patterns in combination with physical inactivity contribute to obesity and metabolic consequences such as increased levels of IGF-1, insulin, estrogen, and possibly testosterone. These hormones tend to promote cellular growth. For prostate cancer, epidemiologic studies consistently show a positive association with high consumption of milk, dairy products, and meats. These dietary factors tend to decrease 1.25(OH)2 vitamin D, a cell differentiator, and low levels of this hormone may enhance prostate carcinogenesis. While the nutritional modulation of growth-enhancing and differentiating hormones is likely to contribute to the high prevalence of breast, colorectal, prostate, and several other cancers in the Western world, these cancers are relatively rare in less economically developed countries, where malignancies of the upper gastrointestinal tract are quite common. The major causes of upper gastrointestinal tract cancers are likely related to various food practices or preservation

  12. Motivating factors among Iranian nurses

    PubMed Central

    Negarandeh, Reza; Dehghan-Nayeri, Nahid; Ghasemi, Elham

    2015-01-01

    Background: One of the most important challenges of Iranian health care system is “quality of care,” and it is assumed that motivated nurses are more ready to provide better care. There are limited studies investigating Iranian nurses’ motivations; however, factors which motivate them have not been studied yet. Identifying the motivating factors enables nurse managers to inspire nurses for continuous quality improvement. The aim of this study was to identify motivating factors for Iranian hospital nurses. Materials and Methods: This is a cross-sectional descriptive study in which 310 nurses working at 14 hospitals of Tehran University of Medical Sciences were selected by proportionate stratified random sampling. Data were collected in 2010 by a researcher-developed questionnaire. Descriptive statistics and independent t-test, analysis of variance, Tukey post-hoc test, Chi-Square and Fisher's exact test were used for statistical analysis by Statistical Package for Social Sciences (SPSS) version 16. Results: The mean score of motivation was 90.53 ± 10.76 (range: 59–121). Four motivating factors including “career development” (22.63 ± 5.66), “job characteristics” (34.29 ± 4), “job authority” (18.48 ± 2.79), and “recognition” (15.12 ± 2.5) were recognized. The least mean of the motivation score, considering the number of items, was 3.23 for career development, while the highest mean was 3.81 for job characteristics. Conclusions: The findings showed that motivation of nurses was at a medium level, which calls for improvement. The factors that have the greatest potential to motivate nurses were identified in this study and they can help managers to achieve the goal of continuous quality improvement. PMID:26257797

  13. Prognostic factors in prostate cancer.

    PubMed

    Braeckman, Johan; Michielsen, Dirk

    2007-01-01

    In the nineteenth century the main goal of medicine was predictive: diagnose the disease and achieve a satisfying prognosis of the patient's chances. Today the effort has shifted to cure the disease. Since the twentieth century, the word prognosis has also been used in nonmedical contexts, for example in corporate finance or elections. The most accurate form of prognosis is achieved statistically. Based on different prognostic factors it should be possible to tell patients how they are expected to do after prostate cancer has been diagnosed and how different treatments may change this outcome. A prognosis is a prediction. The word prognosis comes from the Greek word (see text) and means foreknowing. In the nineteenth century this was the main goal of medicine: diagnose the disease and achieve a satisfying prognosis of the patient's chances. Today the effort has shifted towards seeking a cure. Prognostic factors in (prostate) cancer are defined as "variables that can account for some of the heterogeneity associated with the expected course and outcome of a disease". Bailey defined prognosis as "a reasoned forecast concerning the course, pattern, progression, duration, and end of the disease. Prognostic factors are not only essential to understand the natural history and the course of the disease, but also to predict possible different outcomes of different treatments or perhaps no treatment at all. This is extremely important in a disease like prostate cancer where there is clear evidence that a substantial number of cases discovered by prostate-specific antigen (PSA) testing are unlikely ever to become clinically significant, not to mention mortal. Furthermore, prognostic factors are of paramount importance for correct interpretation of clinical trials and for the construction of future trials. Finally, according to WHO national screening committee criteria for implementing a national screening programme, widely accepted prognostic factors must be defined before

  14. Factors influencing permanent teeth eruption. Part one--general factors.

    PubMed

    Almonaitiene, Ruta; Balciuniene, Irena; Tutkuviene, Janina

    2010-01-01

    Variation in the normal eruption of teeth is a common finding, but significant deviation from established norms should alert the clinician to take some diagnostic procedures in order to evaluate patient health and development. Disturbance in tooth eruption time could be a symptom of general condition or indication of altered physiology and craniofacial development. The aim of this review is to analyze general factors that could influence permanent teeth eruption. The articles from 1965 to 2009 in English related to topic were identified. 84 articles were selected for data collection. Although permanent teeth eruption is under significant genetic control, various general factors such as gender, socioeconomic status, craniofacial morphology, body composition can influence this process. Most significant disturbance in teeth emergence is caused by systemic diseases and syndromes. PMID:21063135

  15. Food ingestion factors of the Korean exposure factors handbook.

    PubMed

    Jang, Jae-Yeon; Jo, Soo-Nam; Kim, Sun-Ja; Myung, Hyung-Nam; Kim, Cho-Il

    2014-01-01

    The purpose of this study was to establish food ingestion factors needed to assess exposure to contaminants through food ingestion. The study reclassified the raw data of the Korean National Health and Nutrition Examination Survey in 2001 into 12 subcategories including grain products, meat products, fish and shellfish, and vegetables for international comparability of exposure evaluation. The criteria for food intake calculation were unified according to the characteristics of food groups, and recommended values for food ingestion factors were calculated through moisture correction and recategorization of cooked, processed, and mixed foods for each group. The average intake rate for grain and grain products was 6.25 g/kg-d per capita and the men's intake rate was approximately 8% higher than that of the women. The average intake rate of meat and meat products was 1.62 g/kg-d per capita and the men's intake rate was 30% higher than that of the women, on average. The average intake rate of fish and shellfish was 1.53 g/kg-d per capita, and the age groups of 1 to 2 and 3 to 6 recorded higher capita intake rates than other age groups, 2.62 g/kg-d and 2.25 g/kg-d, respectively. The average intake rate of vegetables was 6.47 g/kg-d per capita, with the age group of 1 to 2 recording the highest per capita intake rate of 9.79 g/kg-d and that of 13 to 19 recording the lowest mean. The study also offers recommended values for food ingestion factors of other food groups by gender, age, and region. The food ingestion exposure factors will need future updates in consideration of ongoing changes in food consumption behavior. PMID:24570803

  16. Sequential coagulation factor VIIa domain binding to tissue factor

    SciTech Connect

    Oesterlund, Maria; Persson, Egon; Freskgard, Per-Ola . E-mail: msv@ifm.liu.se

    2005-12-02

    Vessel wall tissue factor (TF) is exposed to blood upon vascular damage which enables association with factor VIIa (FVIIa). This leads to initiation of the blood coagulation cascade through localization and allosteric induction of FVIIa procoagulant activity. To examine the docking pathway of the FVIIa-TF complex, various residues in the extracellular part of TF (sTF) that are known to interact with FVIIa were replaced with cysteines labelled with a fluorescent probe. By using stopped-flow fluorescence kinetic measurements in combination with surface plasmon resonance analysis, we studied the association of the resulting sTF variants with FVIIa. We found the docking trajectory to be a sequence of events in which the protease domain of FVIIa initiates contact with sTF. Thereafter, the two proteins are tethered via the first epidermal growth factor-like and finally the {gamma}-carboxyglutamic acid (Gla) domain. The two labelled sTF residues interacting with the protease domain of FVIIa bind or become eventually ordered at different rates, revealing kinetic details pertinent to the allosteric activation of FVIIa by sTF. Moreover, when the Gla domain of FVIIa is removed the difference in the rate of association for the remaining domains is much more pronounced.

  17. About Alzheimer's Disease: Risk Factors and Prevention

    MedlinePlus

    ... About ADEAR About Alzheimer's Disease: Risk Factors and Prevention We can’t control some risk factors for ... as well. NIA Information on Risk Factors and Prevention 2014-2015 Alzheimer's Disease Progress Report: Advancing Research ...

  18. Genetics Home Reference: factor V deficiency

    MedlinePlus

    ... Genetics Home Health Conditions factor V deficiency factor V deficiency Enable Javascript to view the expand/collapse ... Download PDF Open All Close All Description Factor V deficiency is a rare bleeding disorder. The signs ...

  19. Shot-noise Fano factor

    NASA Astrophysics Data System (ADS)

    Rajdl, Kamil; Lansky, Petr

    2015-11-01

    A variability measure of the times of uniform events based on a shot-noise process is proposed and studied. The measure is inspired by the Fano factor, which we generalize by considering the time-weighted influence of the events given by a shot-noise response function. The sequence of events is assumed to be an equilibrium renewal process, and based on this assumption we present formulas describing the behavior of the variability measure. The formulas are derived for a general response function, restricted only by some natural conditions, but the main focus is given to the shot noise with exponential decrease. The proposed measure is analyzed and compared with the Fano factor.

  20. Nutritional Factors Affecting Mental Health.

    PubMed

    Lim, So Young; Kim, Eun Jin; Kim, Arang; Lee, Hee Jae; Choi, Hyun Jin; Yang, Soo Jin

    2016-07-01

    Dietary intake and nutritional status of individuals are important factors affecting mental health and the development of psychiatric disorders. Majority of scientific evidence relating to mental health focuses on depression, cognitive function, and dementia, and limited evidence is available about other psychiatric disorders including schizophrenia. As life span of human being is increasing, the more the prevalence of mental disorders is, the more attention rises. Lists of suggested nutritional components that may be beneficial for mental health are omega-3 fatty acids, phospholipids, cholesterol, niacin, folate, vitamin B6, and vitamin B12. Saturated fat and simple sugar are considered detrimental to cognitive function. Evidence on the effect of cholesterol is conflicting; however, in general, blood cholesterol levels are negatively associated with the risk of depression. Collectively, the aims of this review are to introduce known nutritional factors for mental health, and to discuss recent issues of the nutritional impact on cognitive function and healthy brain aging. PMID:27482518

  1. Endometriosis, Angiogenesis and Tissue Factor

    PubMed Central

    Krikun, Graciela

    2012-01-01

    Tissue factor (TF), is a cellular receptor that binds the factor VII/VIIa to initiate the blood coagulation cascade. In addition to its role as the initiator of the hemostatic cascade, TF is known to be involved in angiogenesis via intracellular signaling that utilizes the protease activated receptor-2 (PAR-2). We now review the physiologic expression of TF in the endometrium and its altered expression in multiple cell types derived from eutopic and ectopic endometrium from women with endometriosis compared with normal endometrium. Our findings suggest that TF might be an ideal target for therapeutic intervention in endometriosis. We have employed a novel immunoconjugate molecule known as Icon and were able to eradicate endometrial lesions in a mouse model of endometriosis without affecting fertility. These findings have major implications for potential treatment in humans. PMID:24278684

  2. Human factors and quality improvement.

    PubMed

    Handyside, James; Suresh, Gautham

    2010-03-01

    Human factors analysis (HFE) presents a formidable contribution to quality improvement (QI) in the neonatal intensive care unit (NICU). The science behind the fundamental principles concerning the design of work systems that match the needs of the people who work in them is sound and is applied widely in other safety critical situations. Early application of HFE in NICUs has shown the usefulness of these methods for frontline teams working to improve quality, reliability, and safety. The inclusion of human factors considerations in the design of structure and process has the potential to improve outcomes for patients and families and to improve the comfort and usability of work systems for providers who work in them. New technologies and continual change must be informed and designed through the application of HFE methods and principles to realize the full potential of QI. PMID:20363451

  3. [Epidemiologic factors in ovarian cancer].

    PubMed

    Curie, P; Sussmann, M; Treisser, A; Renaud, R

    1985-05-01

    Ovarian carcinoma is the most severe gynecological cancer with an overall incidence of 12 per 1000 Americans or Europeans developing it over 40 years of age. Only 3 of the 12 cases will receive efficient care because the diagnosis will be made too late. This study reveals the principal risk factors i.e. upper socioeconomic echelon, ovarian function uninterrupted by a pregnancy or usage of oral contraceptives, anamnestic evidence of ovarian carcinoma in the family, some hereditary disorders, external insults (talcum powder). The synthesis of these various risk factors permits a comprehensive review of the hypotheses of pathogenesis concerning recurrence of tumors. But corollary epidemiologic studies are still needed to try to define better the high risk groups whose follow-up systematic detection and testing is a priority. PMID:4023542

  4. Prognostic factors in histiocytosis X.

    PubMed

    Lahey, M E

    1981-01-01

    It is now clear that the prognosis in children with histiocytosis X has improved considerable over the past few years. To be sure, patients with solitary lesions have an excellent prognosis. Whereas the outlook for patients with significant visceral involvement is not as good as those with bone lesions only, the outlook is by no means hopeless, as was once thought. A number of prognostic factors have been reviewed here. The most significant of these factors at the present time would appear to be age of onset of the disease, extent of involvement, the rapidity of progression of the disease, and, in particular, the presence or absence of dysfunction of such crucial organ systems as liver, lung, and hemopoietic system. Further studies of the significance of histologic features and immunologic findings are clearly needed to further our understanding of this disorder. PMID:6972178

  5. Shot-noise Fano factor.

    PubMed

    Rajdl, Kamil; Lansky, Petr

    2015-11-01

    A variability measure of the times of uniform events based on a shot-noise process is proposed and studied. The measure is inspired by the Fano factor, which we generalize by considering the time-weighted influence of the events given by a shot-noise response function. The sequence of events is assumed to be an equilibrium renewal process, and based on this assumption we present formulas describing the behavior of the variability measure. The formulas are derived for a general response function, restricted only by some natural conditions, but the main focus is given to the shot noise with exponential decrease. The proposed measure is analyzed and compared with the Fano factor. PMID:26651674

  6. Nutritional Factors Affecting Mental Health

    PubMed Central

    Lim, So Young; Kim, Eun Jin; Kim, Arang; Lee, Hee Jae; Choi, Hyun Jin

    2016-01-01

    Dietary intake and nutritional status of individuals are important factors affecting mental health and the development of psychiatric disorders. Majority of scientific evidence relating to mental health focuses on depression, cognitive function, and dementia, and limited evidence is available about other psychiatric disorders including schizophrenia. As life span of human being is increasing, the more the prevalence of mental disorders is, the more attention rises. Lists of suggested nutritional components that may be beneficial for mental health are omega-3 fatty acids, phospholipids, cholesterol, niacin, folate, vitamin B6, and vitamin B12. Saturated fat and simple sugar are considered detrimental to cognitive function. Evidence on the effect of cholesterol is conflicting; however, in general, blood cholesterol levels are negatively associated with the risk of depression. Collectively, the aims of this review are to introduce known nutritional factors for mental health, and to discuss recent issues of the nutritional impact on cognitive function and healthy brain aging. PMID:27482518

  7. Factors influencing pacing in triathlon

    PubMed Central

    Wu, Sam SX; Peiffer, Jeremiah J; Brisswalter, Jeanick; Nosaka, Kazunori; Abbiss, Chris R

    2014-01-01

    Triathlon is a multisport event consisting of sequential swim, cycle, and run disciplines performed over a variety of distances. This complex and unique sport requires athletes to appropriately distribute their speed or energy expenditure (ie, pacing) within each discipline as well as over the entire event. As with most physical activity, the regulation of pacing in triathlon may be influenced by a multitude of intrinsic and extrinsic factors. The majority of current research focuses mainly on the Olympic distance, whilst much less literature is available on other triathlon distances such as the sprint, half-Ironman, and Ironman distances. Furthermore, little is understood regarding the specific physiological, environmental, and interdisciplinary effects on pacing. Therefore, this article discusses the pacing strategies observed in triathlon across different distances, and elucidates the possible factors influencing pacing within the three specific disciplines of a triathlon. PMID:25258562

  8. [Suicide - background, epidemiology, risk factors].

    PubMed

    Ajdacic-Gross, Vladeta

    2015-10-01

    Suicide research, in particular epidemiology, comprises a huge amount of data. However, the theoretical understanding clearly lags behind the empirical knowledge. Suicide, suicide attempts and other suicidal behaviors are more heterogeneous than most explanatory approaches would assume. The most important recent contributions to a better understanding have come from selected epidemiological findings and, interestingly, prevention. This article provides an overview of epidemiological findings, the most relevant risk factors and conclusions related to successful preventive efforts. PMID:26423878

  9. Human factors in incident reporting

    NASA Technical Reports Server (NTRS)

    Jones, S. G.

    1993-01-01

    The paper proposes a cooperative research effort be undertaken by academic institutions and industry organizations toward the compilation of a human factors data base in conjunction with technical information. Team members in any discipline can benefit and learn from observing positive examples of decision making and performance by crews under stressful or less than optimal circumstances. The opportunity to note trends in interpersonal and interactive behaviors and to categorize them is terms of more or less desirable outcomes should not be missed.

  10. Human Factors in Space Exploration

    NASA Technical Reports Server (NTRS)

    Jones, Patricia M.; Fiedler, Edna

    2010-01-01

    The exploration of space is one of the most fascinating domains to study from a human factors perspective. Like other complex work domains such as aviation (Pritchett and Kim, 2008), air traffic management (Durso and Manning, 2008), health care (Morrow, North, and Wickens, 2006), homeland security (Cooke and Winner, 2008), and vehicle control (Lee, 2006), space exploration is a large-scale sociotechnical work domain characterized by complexity, dynamism, uncertainty, and risk in real-time operational contexts (Perrow, 1999; Woods et ai, 1994). Nearly the entire gamut of human factors issues - for example, human-automation interaction (Sheridan and Parasuraman, 2006), telerobotics, display and control design (Smith, Bennett, and Stone, 2006), usability, anthropometry (Chaffin, 2008), biomechanics (Marras and Radwin, 2006), safety engineering, emergency operations, maintenance human factors, situation awareness (Tenney and Pew, 2006), crew resource management (Salas et aI., 2006), methods for cognitive work analysis (Bisantz and Roth, 2008) and the like -- are applicable to astronauts, mission control, operational medicine, Space Shuttle manufacturing and assembly operations, and space suit designers as they are in other work domains (e.g., Bloomberg, 2003; Bos et al, 2006; Brooks and Ince, 1992; Casler and Cook, 1999; Jones, 1994; McCurdy et ai, 2006; Neerincx et aI., 2006; Olofinboba and Dorneich, 2005; Patterson, Watts-Perotti and Woods, 1999; Patterson and Woods, 2001; Seagull et ai, 2007; Sierhuis, Clancey and Sims, 2002). The human exploration of space also has unique challenges of particular interest to human factors research and practice. This chapter provides an overview of those issues and reports on sorne of the latest research results as well as the latest challenges still facing the field.

  11. Nutritional factors and hair loss.

    PubMed

    Rushton, D H

    2002-07-01

    The literature reveals what little is known about nutritional factors and hair loss. What we do know emanates from studies in protein-energy malnutrition, starvation, and eating disorders. In otherwise healthy individuals, nutritional factors appear to play a role in subjects with persistent increased hair shedding. Hård, 40 years ago, demonstrated the importance of iron supplements in nonanaemic, iron-deficient women with hair loss. Serum ferritin concentrations provide a good assessment of an individual's iron status. Rushton et al. first published data showing that serum ferritin concentrations were a factor in female hair loss and, 10 years later, Kantor et al. confirmed this association. What level of serum ferritin to employ in subjects with increased hair shedding is yet to be definitively established but 70 micro g/L, with a normal erythrocyte sedimentation rate (< 10 mm/h), is recommended. The role of the essential amino acid, l-lysine in hair loss also appears to be important. Double-blind data confirmed the findings of an open study in women with increased hair shedding, where a significant proportion responded to l-lysine and iron therapy. There is no evidence to support the popular view that low serum zinc concentrations cause hair loss. Excessive intakes of nutritional supplements may actually cause hair loss and are not recommended in the absence of a proven deficiency. While nutritional factors affect the hair directly, one should not forget that they also affect the skin. In the management of subjects with hair loss, eliminating scaling problems is important as is good hair care advice and the need to explain fully the hair cycle. Many individuals reduced their shampooing frequency due to fear of losing more hair but this increases the amount seen in subsequent shampoos fuelling their fear of going bald and adversely affecting their quality of life. PMID:12190640

  12. Factor weighting in DRASTIC modeling.

    PubMed

    Pacheco, F A L; Pires, L M G R; Santos, R M B; Sanches Fernandes, L F

    2015-02-01

    Evaluation of aquifer vulnerability comprehends the integration of very diverse data, including soil characteristics (texture), hydrologic settings (recharge), aquifer properties (hydraulic conductivity), environmental parameters (relief), and ground water quality (nitrate contamination). It is therefore a multi-geosphere problem to be handled by a multidisciplinary team. The DRASTIC model remains the most popular technique in use for aquifer vulnerability assessments. The algorithm calculates an intrinsic vulnerability index based on a weighted addition of seven factors. In many studies, the method is subject to adjustments, especially in the factor weights, to meet the particularities of the studied regions. However, adjustments made by different techniques may lead to markedly different vulnerabilities and hence to insecurity in the selection of an appropriate technique. This paper reports the comparison of 5 weighting techniques, an enterprise not attempted before. The studied area comprises 26 aquifer systems located in Portugal. The tested approaches include: the Delphi consensus (original DRASTIC, used as reference), Sensitivity Analysis, Spearman correlations, Logistic Regression and Correspondence Analysis (used as adjustment techniques). In all cases but Sensitivity Analysis, adjustment techniques have privileged the factors representing soil characteristics, hydrologic settings, aquifer properties and environmental parameters, by leveling their weights to ≈4.4, and have subordinated the factors describing the aquifer media by downgrading their weights to ≈1.5. Logistic Regression predicts the highest and Sensitivity Analysis the lowest vulnerabilities. Overall, the vulnerability indices may be separated by a maximum value of 51 points. This represents an uncertainty of 2.5 vulnerability classes, because they are 20 points wide. Given this ambiguity, the selection of a weighting technique to integrate a vulnerability index may require additional

  13. Factors affecting maximal acid secretion

    PubMed Central

    Desai, H. G.

    1969-01-01

    The mechanisms by which different factors affect the maximal acid secretion of the stomach are discussed with particular reference to nationality, sex, age, body weight or lean body mass, procedural details, mode of calculation, the nature, dose and route of administration of a stimulus, the synergistic action of another stimulus, drugs, hormones, electrolyte levels, anaemia or deficiency of the iron-dependent enzyme system, vagal continuity and parietal cell mass. PMID:4898322

  14. [Nutritional factors in preventing osteoporosis].

    PubMed

    Martín Jiménez, Juan Antonio; Consuegra Moya, Belkis; Martín Jiménez, María Teresa

    2015-01-01

    Osteoporosis, main risk factor for suffering fragility fractures, is an important public health problem which has undoubted social, health and economic impact; but mainly causes pain, functional limitation and severe alterations in the patient's quality of life. Its current prevalence is very high and a further increase is expected due to a higher life expectancy and the progressive ageing of the population. In the prevention of osteoporosis, the main goal is to prevent fragility fractures; for this reason, it is necessary to: 1) promote bone formation in youth, to get sufficient bone mass peak, 2) reduce bone loss in adulthood, especially after menopause, 3) maintain bone health throughout life, and 4) prevent falls. There is enough evidence that multifactorial strategies (assessment of risk factors, healthy lifestyle habits, smoking cessation, moderation in alcohol consumption, physical exercise, outdoor activity with prudent exposure to sunlight, and a varied and balanced diet), are effective in the population at risk. Regarding factors for the prevention of osteoporosis, current recommendations are: increased consumption of calcium, phosphorus, magnesium and fluoride; provide adequate vitamin D (even with fortified food if necessary); consumption of foods rich in omega-3 acids; reduction of salt and prepared ready meals; sufficient but moderate intake of protein and, in the absence of intolerance, promote the consumption of milk and dairy products, especially yogurt and fermented milk products. PMID:26267775

  15. Human Factors in Financial Trading

    PubMed Central

    Leaver, Meghan; Reader, Tom W.

    2016-01-01

    Objective This study tests the reliability of a system (FINANS) to collect and analyze incident reports in the financial trading domain and is guided by a human factors taxonomy used to describe error in the trading domain. Background Research indicates the utility of applying human factors theory to understand error in finance, yet empirical research is lacking. We report on the development of the first system for capturing and analyzing human factors–related issues in operational trading incidents. Method In the first study, 20 incidents are analyzed by an expert user group against a referent standard to establish the reliability of FINANS. In the second study, 750 incidents are analyzed using distribution, mean, pathway, and associative analysis to describe the data. Results Kappa scores indicate that categories within FINANS can be reliably used to identify and extract data on human factors–related problems underlying trading incidents. Approximately 1% of trades (n = 750) lead to an incident. Slip/lapse (61%), situation awareness (51%), and teamwork (40%) were found to be the most common problems underlying incidents. For the most serious incidents, problems in situation awareness and teamwork were most common. Conclusion We show that (a) experts in the trading domain can reliably and accurately code human factors in incidents, (b) 1% of trades incur error, and (c) poor teamwork skills and situation awareness underpin the most critical incidents. Application This research provides data crucial for ameliorating risk within financial trading organizations, with implications for regulation and policy. PMID:27142394

  16. Macrophages from IBD patients exhibit defective tumour necrosis factor-α secretion but otherwise normal or augmented pro-inflammatory responses to infection.

    PubMed

    Campos, Nair; Magro, Fernando; Castro, Ana Rita; Cabral, Joana; Rodrigues, Pedro; Silva, Ricardo; Appelberg, Rui; Rodrigues, Susana; Lopes, Susana; Macedo, Guilherme; Sarmento, Amélia

    2011-08-01

    Defects in macrophage function have been implicated in the establishment of Crohn's disease (CD). However, the response of macrophages from CD patients to live bacteria, particularly Mycobacterium avium subsp. paratuberculosis (MAP), has not been addressed. Considering MAP has long been associated to CD, our objective was to assess whether macrophages from CD patients showed impaired inflammatory response to infection by MAP comparing to M. avium subsp. avium (MA) and other live intestinal commensal bacteria. Human peripheral blood monocyte-derived macrophages were obtained from CD patients, ulcerative colitis (UC) patients and controls. Following in vitro infection with MAP, MA, Escherichia coli or Enterococcus faecalis, cytokine levels and cell surface receptor expression were evaluated at different time points. Macrophages from CD patients showed impaired TNF-α secretion in response to bacterial challenge, but augmented IL-23 secretion and preserved IL-12 secretion and CD-40 expression. In addition, CD macrophages showed low IL-10 secretion. Macrophages from IBD patients showed increased expression of TLR-2 and -4, unaffected by infection. Differences in cytokine secretion observed after bacterial challenge were not MAP-specific, as other bacteria (E. coli and MA) showed similar effects. Macrophages from UC patients showed a less compromised TNF-α synthesis in response to mycobacterial infection than CD macrophages, with increased constitutive IL-12 secretion, and preserved IL-10 secretion. The increased IL-23 levels in response to infection and decreased IL-10 production observed in macrophages from CD patients may contribute to the inflammatory exacerbation observed in those patients. PMID:21269730

  17. Environmental factors in multiple sclerosis.

    PubMed

    Pantazou, Vasiliki; Schluep, Myriam; Du Pasquier, Renaud

    2015-04-01

    Although multiple sclerosis (MS) is recognized as a disorder involving the immune system, the interplay of environmental factors and individual genetic susceptibility seems to influence MS onset and clinical expression, as well as therapeutic responsiveness. Multiple human epidemiological and animal model studies have evaluated the effect of different environmental factors, such as viral infections, vitamin intake, sun exposure, or still dietary and life habits on MS prevalence. Previous Epstein-Barr virus infection, especially if this infection occurs in late childhood, and lack of vitamin D (VitD) currently appear to be the most robust environmental factors for the risk of MS, at least from an epidemiological standpoint. Ultraviolet radiation (UVR) activates VitD production but there are also some elements supporting the fact that insufficient UVR exposure during childhood may represent a VitD-independent risk factor of MS development, as well as negative effect on the clinical and radiological course of MS. Recently, there has been a growing interest in the gut-brain axis, a bidirectional neuro-hormonal communication system between the intestinal microbiota and the central nervous system (CNS). Indeed, components of the intestinal microbiota may be pro-inflammatory, promote the migration of immune cells into the CNS, and thus be a key parameter for the development of autoimmune disorders such as MS. Interestingly most environmental factors seem to play a role during childhood. Thus, if childhood is the most fragile period to develop MS later in life, preventive measures should be applied early in life. For example, adopting a diet enriched in VitD, playing outdoor and avoiding passive smoking would be extremely simple measures of primary prevention for public health strategies. However, these hypotheses need to be confirmed by prospective evaluations, which are obviously difficult to conduct. In addition, it remains to be determined whether and how Vit

  18. Cardiac risk factors: environmental, sociodemographic, and behavioral cardiovascular risk factors.

    PubMed

    Anthony, David; George, Paul; Eaton, Charles B

    2014-06-01

    Several environmental exposures are associated with increased risk of coronary heart disease (CHD). Exposure to secondhand smoke may increase the risk by as much as 25% to 30%. Exposure to third hand smoke, residual components of tobacco smoke that remain in the environment after a cigarette is extinguished, also appears to increase risk. These residual components can remain in rooms and automobiles for up to 30 years and enter the body through the skin or via inhalation or ingestion. Exposure to particulate matter air pollution from automobile emissions, power plants, and other sources is yet another environmental risk factor for CHD, resulting in tens of thousands of deaths annually in the United States. Exposure to other environmental toxins, particularly bisphenol A and phthalates, also has been linked to CHD. There are sociodemographic risks for CHD, with numerous studies showing that lower socioeconomic status is associated with higher risk. Behavioral risk factors include poor diet, such as frequent consumption of fast food and processed meals; sleep disturbance; and psychological stress, particularly related to marital or work issues. Finally, although high alcohol consumption is associated with increased CHD risk, moderate alcohol consumption (ie, less than 1 to 2 drinks/day), particularly of wine and possibly beer, appears to reduce the risk. PMID:24936715

  19. Scene kinetics mitigation using factor analysis with derivative factors.

    SciTech Connect

    Larson, Kurt W.; Melgaard, David Kennett; Scholand, Andrew Joseph

    2010-07-01

    Line of sight jitter in staring sensor data combined with scene information can obscure critical information for change analysis or target detection. Consequently before the data analysis, the jitter effects must be significantly reduced. Conventional principal component analysis (PCA) has been used to obtain basis vectors for background estimation; however PCA requires image frames that contain the jitter variation that is to be modeled. Since jitter is usually chaotic and asymmetric, a data set containing all the variation without the changes to be detected is typically not available. An alternative approach, Scene Kinetics Mitigation, first obtains an image of the scene. Then it computes derivatives of that image in the horizontal and vertical directions. The basis set for estimation of the background and the jitter consists of the image and its derivative factors. This approach has several advantages including: (1) only a small number of images are required to develop the model, (2) the model can estimate backgrounds with jitter different from the input training images, (3) the method is particularly effective for sub-pixel jitter, and (4) the model can be developed from images before the change detection process. In addition the scores from projecting the factors on the background provide estimates of the jitter magnitude and direction for registration of the images. In this paper we will present a discussion of the theoretical basis for this technique, provide examples of its application, and discuss its limitations.

  20. Dopamine receptor regulating factor, DRRF: a zinc finger transcription factor.

    PubMed

    Hwang, C K; D'Souza, U M; Eisch, A J; Yajima, S; Lammers, C H; Yang, Y; Lee, S H; Kim, Y M; Nestler, E J; Mouradian, M M

    2001-06-19

    Dopamine receptor genes are under complex transcription control, determining their unique regional distribution in the brain. We describe here a zinc finger type transcription factor, designated dopamine receptor regulating factor (DRRF), which binds to GC and GT boxes in the D1A and D2 dopamine receptor promoters and effectively displaces Sp1 and Sp3 from these sequences. Consequently, DRRF can modulate the activity of these dopamine receptor promoters. Highest DRRF mRNA levels are found in brain with a specific regional distribution including olfactory bulb and tubercle, nucleus accumbens, striatum, hippocampus, amygdala, and frontal cortex. Many of these brain regions also express abundant levels of various dopamine receptors. In vivo, DRRF itself can be regulated by manipulations of dopaminergic transmission. Mice treated with drugs that increase extracellular striatal dopamine levels (cocaine), block dopamine receptors (haloperidol), or destroy dopamine terminals (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) show significant alterations in DRRF mRNA. The latter observations provide a basis for dopamine receptor regulation after these manipulations. We conclude that DRRF is important for modulating dopaminergic transmission in the brain. PMID:11390978

  1. Academic Success Factors: An IT Student Perspective

    ERIC Educational Resources Information Center

    Zhang, Aimao; Aasheim, Cheryl L.

    2011-01-01

    Numerous studies have identified causal factors for academic success. Factors vary from personal factors, such as cognitive style (McKenzie & Schweitzer, 2001), to social factors, such as culture differences (Aysan, Tanriogen, & Tanriogen, 1996). However, in these studies it is re-searchers who theorized the causal dimensions and hypothesized the…

  2. Factor Analysis of Law School Grades.

    ERIC Educational Resources Information Center

    Boldt, Robert F.

    Grades of 116 law school students were obtained from transcripts, along with LSAT, Writing Ability and Background scores. The grades were factored, and an analysis of the goodness of fit of one- through four-factor systems indicated that the system of grades was essentially one factor in nature. A plot of factor loadings for the various courses…

  3. Remarks on KERMA Factors in ACE files

    NASA Astrophysics Data System (ADS)

    Konno, C.; Ochiai, K.; Takakura, K.; Sato, S.

    2014-04-01

    Some neutron KERMA factors in ACE files are negative and extremely large if nuclear data libraries do not keep energy-balance. The status of neutron KERMA factors in the official ACE file of ENDF/B-VII.1 is examined. As a result, it is found out that neutron KERMA factors of nuclei more than 200 in ENDF/B-VII.1 have some problems. Effects of the inadequate KERMA factor are also investigated, which are large for neutron heat while those are small for total (neutron + gamma) heat. Users who use only neutron KERMA factors should check if the factors are adequate or not before they use the factors.

  4. Understanding adverse events: human factors.

    PubMed Central

    Reason, J

    1995-01-01

    (1) Human rather than technical failures now represent the greatest threat to complex and potentially hazardous systems. This includes healthcare systems. (2) Managing the human risks will never be 100% effective. Human fallibility can be moderated, but it cannot be eliminated. (3) Different error types have different underlying mechanisms, occur in different parts of the organisation, and require different methods of risk management. The basic distinctions are between: Slips, lapses, trips, and fumbles (execution failures) and mistakes (planning or problem solving failures). Mistakes are divided into rule based mistakes and knowledge based mistakes. Errors (information-handling problems) and violations (motivational problems) Active versus latent failures. Active failures are committed by those in direct contact with the patient, latent failures arise in organisational and managerial spheres and their adverse effects may take a long time to become evident. (4) Safety significant errors occur at all levels of the system, not just at the sharp end. Decisions made in the upper echelons of the organisation create the conditions in the workplace that subsequently promote individual errors and violations. Latent failures are present long before an accident and are hence prime candidates for principled risk management. (5) Measures that involve sanctions and exhortations (that is, moralistic measures directed to those at the sharp end) have only very limited effectiveness, especially so in the case of highly trained professionals. (6) Human factors problems are a product of a chain of causes in which the individual psychological factors (that is, momentary inattention, forgetting, etc) are the last and least manageable links. Attentional "capture" (preoccupation or distraction) is a necessary condition for the commission of slips and lapses. Yet, its occurrence is almost impossible to predict or control effectively. The same is true of the factors associated with

  5. Modifications of Coronary Risk Factors

    PubMed Central

    Albu, Jeanine; Gottlieb, Sheldon H.; August, Phyllis; Nesto, Richard W.; Orchard, Trevor J.

    2009-01-01

    In addition to the revascularization and glycemic management interventions assigned at random, the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) design includes the uniform control of major coronary artery disease risk factors, including dyslipidemia, hypertension, smoking, central obesity, and sedentary lifestyle. Target levels for risk factors were adjusted throughout the trial to comply with changes in recommended clinical practice guidelines. At present, the goals are low-density lipoprotein cholesterol <2.59 mmol/L (<100 mg/dL) with an optional goal of <1.81 mmol/L (<70 mg/dL); plasma triglyceride level <1.70 mmol/L (<150 mg/dL); blood pressure level <130 mm Hg systolic and <80 mm Hg diastolic; and smoking cessation treatment for all active smokers. Algorithms were developed for the pharmacologic management of dyslipidemia and hypertension. Dietary prescriptions for the management of glycemia, plasma lipid profiles, and blood pressure levels were adapted from existing clinical practice guidelines. Patients with a body mass index >25 were prescribed moderate caloric restriction; after the trial was under way, a lifestyle weight-management program was instituted. All patients were formally prescribed both endurance and resistance/flexibility exercises, individually adapted to their level of disability and fitness. Pedometers were distributed as a biofeedback strategy. Strategies to achieve the goals for risk factors were designed by BARI 2D working groups (lipid, cardiovascular and hypertension, and nonpharmacologic intervention) and the ongoing implementation of the strategies is monitored by lipid, hypertension, and lifestyle intervention management centers. PMID:16813737

  6. Small Peptides Blocking Inhibition of Factor Xa and Tissue Factor-Factor VIIa by Tissue Factor Pathway Inhibitor (TFPI)*

    PubMed Central

    Dockal, Michael; Hartmann, Rudolf; Fries, Markus; Thomassen, M. Christella L. G. D.; Heinzmann, Alexandra; Ehrlich, Hartmut; Rosing, Jan; Osterkamp, Frank; Polakowski, Thomas; Reineke, Ulrich; Griessner, Andreas; Brandstetter, Hans; Scheiflinger, Friedrich

    2014-01-01

    Tissue factor pathway inhibitor (TFPI) is a Kunitz-type protease inhibitor that inhibits activated factor X (FXa) via a slow-tight binding mechanism and tissue factor-activated FVII (TF-FVIIa) via formation of a quaternary FXa-TFPI-TF-FVIIa complex. Inhibition of TFPI enhances coagulation in hemophilia models. Using a library approach, we selected and subsequently optimized peptides that bind TFPI and block its anticoagulant activity. One peptide (termed compound 3), bound with high affinity to the Kunitz-1 (K1) domain of TFPI (Kd ∼1 nm). We solved the crystal structure of this peptide in complex with the K1 of TFPI at 2.55-Å resolution. The structure of compound 3 can be segmented into a N-terminal anchor; an Ω-shaped loop; an intermediate segment; a tight glycine-loop; and a C-terminal α-helix that is anchored to K1 at its reactive center loop and two-stranded β-sheet. The contact surface has an overall hydrophobic character with some charged hot spots. In a model system, compound 3 blocked FXa inhibition by TFPI (EC50 = 11 nm) and inhibition of TF-FVIIa-catalyzed FX activation by TFPI (EC50 = 2 nm). The peptide prevented transition from the loose to the tight FXa-TFPI complex, but did not affect formation of the loose FXa-TFPI complex. The K1 domain of TFPI binds and inhibits FVIIa and the K2 domain similarly inhibits FXa. Because compound 3 binds to K1, our data show that K1 is not only important for FVIIa inhibition but also for FXa inhibition, i.e. for the transition of the loose to the tight FXa-TFPI complex. This mode of action translates into normalization of coagulation of hemophilia plasmas. Compound 3 thus bears potential to prevent bleeding in hemophilia patients. PMID:24275667

  7. Type I Interferons Function as Autocrine and Paracrine Factors to Induce Autotaxin in Response to TLR Activation

    PubMed Central

    Song, Jianwen; Guan, Ming; Zhao, Zhenwen; Zhang, Junjie

    2015-01-01

    Lysophosphatidic acid (LPA) is an important phospholipid mediator in inflammation and immunity. However, the mechanism of LPA regulation during inflammatory response is largely unknown. Autotaxin (ATX) is the key enzyme to produce extracellular LPA from lysophosphatidylcholine (LPC). In this study, we found that ATX was induced in monocytic THP-1 cells by TLR4 ligand lipopolysaccharide (LPS), TLR9 ligand CpG oligonucleotide, and TLR3 ligand poly(I:C), respectively. The ATX induction by TLR ligand was abolished by the neutralizing antibody against IFN-β or the knockdown of IFNAR1, indicating that type I IFN autocrine loop is responsible for the ATX induction upon TLR activation. Both IFN-β and IFN-α were able to induce ATX expression via the JAK-STAT and PI3K-AKT pathways but with different time-dependent manners. The ATX induction by IFN-β was dramatically enhanced by IFN-γ, which had no significant effect on ATX expression alone, suggesting a synergy effect between type I and type II IFNs in ATX induction. Extracellular LPA levels were significantly increased when THP-1 cells were treated with IFN-α/β or TLR ligands. In addition, the type I IFN-mediated ATX induction was identified in human monocyte-derived dendritic cells (moDCs) stimulated with LPS or poly(I:C), and IFN-α/β could induce ATX expression in human peripheral blood mononuclear cells (PBMCs) and monocytes isolated form blood samples. These results suggest that, in response to TLR activation, ATX is induced through a type I INF autocrine-paracrine loop to enhance LPA generation. PMID:26313906

  8. Human Factors in Space Flight

    NASA Technical Reports Server (NTRS)

    Woolford, Barbara J.; Mount, Frances

    2005-01-01

    After forty years of experience with human space flight (Table 1), the current emphasis is on the design of space vehicles, habitats, and missions to ensure mission success. What lessons have we learned that will affect the design of spacecraft for future space exploration, leading up to exploring Mars? This chapter addresses this issue in four sections: Anthropometry and Biomechanics; Environmental Factors; Habitability and Architecture; and Crew Personal Sustenance. This introductory section introduces factors unique to space flight. A unique consideration for design of a habitable volume in a space vehicle is the lack of gravity during a space flight, referred to as microgravity. This affects all aspects of life, and drives special features in the habitat, equipment, tools, and procedures. The difference in gravity during a space mission requires designing for posture and motion differences. In Earth s gravity, or even with partial gravity, orientation is not a variable because the direction in which gravity acts defines up and down. In a microgravity environment the working position is arbitrary; there is no gravity cue. Orientation is defined primarily through visual cues. The orientation within a particular crew station or work area is referred to as local vertical, and should be consistent within a module to increase crew productivity. Equipment was intentionally arranged in various orientations in one module on Skylab to assess the efficiency in use of space versus the effects of inconsistent layout. The effects of that arrangement were confusion on entering the module, time spent in re-orientation, and conflicts in crew space requirements when multiple crew members were in the module. Design of a space vehicle is constrained by the three major mission drivers: mass, volume and power. Each of these factors drives the cost of a mission. Mass and volume determine the size of the launch vehicle directly; they can limit consumables such as air, water, and

  9. Psychological factors in emergency medicine.

    PubMed

    Gutenstein, Marc

    2014-06-01

    Human psychology, neuroscience and behavioural economics study the human mind, brain and behaviour. Scientific research has discovered a great deal about the factors that influence human perception, judgment and activity in the real world. In this article, I aim to provide an outline of the relationship between decision-making, cognition, emotion and behaviour. I propose that meta-cognition, or thinking-about-thinking, has the potential to inform how we practice emergency medicine. By accommodating human traits rather than trying to defy them, we can ultimately benefit our patients. PMID:24712897

  10. [Environmental factors in Asperger syndrome].

    PubMed

    Abe, Takaaki; Kato, Satoshi

    2007-03-01

    This paper reviews what is currently known about the environmental factors in Asperger syndrome that is a neurodevelopmental disorder of genetic origins. Its characteristics tend to occur in families of those with the syndrome. The rate of complications during pregnancy or the neonatal period in the patients with Asperger syndrome was about the same as that in the control group. It is true that their involvement in their outer world could not influence the core social deficits very much. But it might facilitate the appearance of the second symptoms such as dissociation, anxiety, depression, persecutory delusion as well as antisocial behavior including serious criminal acts. PMID:17354554

  11. Human factors in spacecraft design

    NASA Technical Reports Server (NTRS)

    Harrison, Albert A.; Connors, Mary M.

    1990-01-01

    This paper describes some of the salient implications of evolving mission parameters for spacecraft design. Among the requirements for future spacecraft are new, higher standards of living, increased support of human productivity, and greater accommodation of physical and cultural variability. Design issues include volumetric allowances, architecture and layouts, closed life support systems, health maintenance systems, recreational facilities, automation, privacy, and decor. An understanding of behavioral responses to design elements is a precondition for critical design decisions. Human factors research results must be taken into account early in the course of the design process.

  12. Targeting Transcription Factors in Cancer

    PubMed Central

    Bhagwat, Anand S.; Vakoc, Christopher R.

    2015-01-01

    Transcription factors (TFs) are commonly deregulated in the pathogenesis of human cancer and are a major class of cancer cell dependencies. Consequently, targeting of TFs can be highly effective in treating particular malignancies, as highlighted by the clinical efficacy of agents that target nuclear hormone receptors. In this review we discuss recent advances in our understanding of TFs as drug targets in oncology, with an emphasis on the emerging chemical approaches to modulate TF function. The remarkable diversity and potency of TFs as drivers of cell transformation justifies a continued pursuit of TFs as therapeutic targets for drug discovery. PMID:26645049

  13. Biographical factors of occupational independence.

    PubMed

    Müller, G F

    2001-10-01

    The present study examined biographical factors of occupational independence including any kind of nonemployed profession. Participants were 59 occupationally independent and 58 employed persons of different age (M = 36.3 yr.), sex, and profession. They were interviewed on variables like family influence, educational background, occupational role models, and critical events for choosing a particular type of occupational career. The obtained results show that occupationally independent people reported stronger family ties, experienced fewer restrictions of formal education, and remembered fewer negative role models than the employed people. Implications of these results are discussed. PMID:11783553

  14. Human factors in spacecraft design.

    PubMed

    Harrison, A A; Connors, M M

    1990-01-01

    This paper describes some of the salient implications of evolving mission parameters for spacecraft design. Among the requirements for future spacecraft are new, higher standards of living, increased support of human productivity, and greater accommodation of physical and cultural variability. Design issues include volumetric allowances, architecture and layouts, closed life support systems, health maintenance systems, recreational facilities, automation, privacy, and decor. An understanding of behavioral responses to design elements is a precondition for critical design decisions. Human factors research results must be taken into account early in the course of the design process. PMID:11537619

  15. Weak-shock reflection factors

    SciTech Connect

    Reichenbach, H.; Kuhl, A.L.

    1993-09-07

    The purpose of this paper is to compare reflection factors for weak shocks from various surfaces, and to focus attention on some unsolved questions. Three different cases are considered: square-wave planar shock reflection from wedges; square-wave planar shock reflection from cylinders; and spherical blast wave reflection from a planar surface. We restrict ourselves to weak shocks. Shocks with a Mach number of M{sub O} < 1.56 in air or with an overpressure of {Delta}{sub PI} < 25 psi (1.66 bar) under normal ambient conditions are called weak.

  16. Human factors in space telepresence

    NASA Technical Reports Server (NTRS)

    Akin, D. L.; Howard, R. D.; Oliveria, J. S.

    1983-01-01

    The problems of interfacing a human with a teleoperation system, for work in space are discussed. Much of the information presented here is the result of experience gained by the M.I.T. Space Systems Laboratory during the past two years of work on the ARAMIS (Automation, Robotics, and Machine Intelligence Systems) project. Many factors impact the design of the man-machine interface for a teleoperator. The effects of each are described in turn. An annotated bibliography gives the key references that were used. No conclusions are presented as a best design, since much depends on the particular application desired, and the relevant technology is swiftly changing.

  17. Factorization of the tenth Fermat number

    NASA Astrophysics Data System (ADS)

    Brent, Richard P.

    We describe the complete factorization of the tenth Fermat number F_{10} by the elliptic curve method (ECM). F_{10} is a product of four prime factors with 8, 10, 40 and 252 decimal digits. The 40-digit factor was found after about 140 Mflop-years of computation. We also discuss the complete factorization of other Fermat numbers by ECM, and summarize the factorizations of F_5, ..., F_{11}.

  18. Human Factors Checklist: Think Human Factors - Focus on the People

    NASA Technical Reports Server (NTRS)

    Miller, Darcy; Stelges, Katrine; Barth, Timothy; Stambolian, Damon; Henderson, Gena; Dischinger, Charles; Kanki, Barbara; Kramer, Ian

    2016-01-01

    A quick-look Human Factors (HF) Checklist condenses industry and NASA Agency standards consisting of thousands of requirements into 14 main categories. With support from contractor HF and Safety Practitioners, NASA developed a means to share key HF messages with Design, Engineering, Safety, Project Management, and others. It is often difficult to complete timely assessments due to the large volume of HF information. The HF Checklist evolved over time into a simple way to consider the most important concepts. A wide audience can apply the checklist early in design or through planning phases, even before hardware or processes are finalized or implemented. The checklist is a good place to start to supplement formal HF evaluation. The HF Checklist was based on many Space Shuttle processing experiences and lessons learned. It is now being applied to ground processing of new space vehicles and adjusted for new facilities and systems.

  19. Factor VIII/factor IX prophylaxis for severe hemophilia.

    PubMed

    Carcao, Manuel; Srivastava, Alok

    2016-01-01

    Experience with clotting factor concentrate (CFC) replacement products over several decades has shown that regular replacement (prophylaxis) is the only way to prevent musculoskeletal damage in hemophilia and impact the natural history of hemophilia. Yet there is a lack of data on the optimal age to start such replacement therapy and the regimens to be used. While very early administration of high doses is certainly more effective in preventing bleeding, cost and compliance are major constraints all over the world. Starting prophylaxis with even lower doses comparable to that used in episodic therapies leads to major reduction in bleeding. Recognition of the clinical heterogeneity of hemophilia even among patients with a label of severe hemophilia in terms of their spontaneous bleeding has led to efforts aimed at individualizing CFC replacement, based on clinical responses or pharmacokinetic data of the CFC. The importance of long-term outcome assessment being combined with CFC replacement therapy cannot be overemphasized. PMID:26805901

  20. Cardiovascular risk factors among Chamorros

    PubMed Central

    Chiem, Binh; Nguyen, Victoria; Wu, Phillis L; Ko, Celine M; Cruz, Lee Ann; Sadler, Georgia Robins

    2006-01-01

    Background Little is known regarding the cardiovascular disease risk factors among Chamorros residing in the United States. Methods The Chamorro Directory International and the CDC's Behavioral Risk Factor Surveillance System Questionnaire (BRFSS) were used to assess the health related practices and needs of a random sample of 228 Chamorros. Results Inactivity, hypertension, elevated cholesterol and diabetes mellitus were more prevalent in this Chamorro sample compared to the US average. Participants who were 50-and-older or unemployed were more likely to report hypertension, diabetes and inactivity, but they were also more likely to consume more fruits and vegetables than their younger and employed counterparts. Women were more likely to report hypertension and diabetes, whereas men were more likely to have elevated BMI and to have never had their blood cholesterol checked. Conclusion The study provides data that will help healthcare providers, public health workers and community leaders identify where to focus their health improvement efforts for Chamorros and create culturally competent programs to promote health in this community. PMID:17156462

  1. Hadamard Factorization of Stable Polynomials

    NASA Astrophysics Data System (ADS)

    Loredo-Villalobos, Carlos Arturo; Aguirre-Hernández, Baltazar

    2011-11-01

    The stable (Hurwitz) polynomials are important in the study of differential equations systems and control theory (see [7] and [19]). A property of these polynomials is related to Hadamard product. Consider two polynomials p,q ∈ R[x]:p(x) = anxn+an-1xn-1+...+a1x+a0q(x) = bmx m+bm-1xm-1+...+b1x+b0the Hadamard product (p × q) is defined as (p×q)(x) = akbkxk+ak-1bk-1xk-1+...+a1b1x+a0b0where k = min(m,n). Some results (see [16]) shows that if p,q ∈R[x] are stable polynomials then (p×q) is stable, also, i.e. the Hadamard product is closed; however, the reciprocal is not always true, that is, not all stable polynomial has a factorization into two stable polynomials the same degree n, if n> 4 (see [15]).In this work we will give some conditions to Hadamard factorization existence for stable polynomials.

  2. Factors affecting outcomes in colonoscopy.

    PubMed

    Selehi, Seema; Leung, Edmund; Wong, Ling

    2008-01-01

    There are many factors that influence successful outcomes in colonoscopy. The aims of this study were to evaluate these factors and determine ways to improve outcomes. All participants (N=229) who underwent planned colonoscopy between July and September 2004 were retrospectively included. Participants included 118 men and 111 women with a mean age of 59 years. Completion rate was 92%. Reasons of failure included poor bowel preparation (2.2%, p< .025), bowel looping (2.2%, p< .025), participant discomfort (1.3%), and obstructing lesion (1.3%). Mean midazolam dose was 3.8 mg. Three participants (1.3%) had midazolam alone, and all had complete colonoscopy. One hundred thirty-three participants (60.7%) had additional meperidine, with a completion rate of 94%. Eighty three participants (37.9%) had additional meperidine and Buscopan, with a completion rate reduced to 89.2%. There was no correlation between sedatives used and completion rate. Completion rate of colonoscopy in our unit was acceptable at 92%. A combination of midazolam and meperidine gave the best completion rates (94%). The two main reasons for incompletion were poor bowel preparation and excessive bowel looping. PMID:18300826

  3. Salmonella-secreted Virulence Factors

    SciTech Connect

    Heffron, Fred; Niemann, George; Yoon, Hyunjin; Kidwai, Afshan S.; Brown, Roslyn N.; McDermott, Jason E.; Smith, Richard D.; Adkins, Joshua N.

    2011-05-01

    In this short review we discuss secreted virulence factors of Salmonella, which directly affect Salmonella interaction with its host. Salmonella secretes protein to subvert host defenses but also, as discussed, to reduce virulence thereby permitting the bacteria to persist longer and more successfully disperse. The type III secretion system (TTSS) is the best known and well studied of the mechanisms that enable secretion from the bacterial cytoplasm to the host cell cytoplasm. Other secretion systems include outer membrane vesicles, which are present in all Gram-negative bacteria examined to date, two-partner secretion, and type VI secretion will also be addressed. Excellent reviews of Salmonella secreted effectors have focused on themes such as actin rearrangements, vesicular trafficking, ubiquitination, and the activities of the virulence factors themselves. This short review is based on S. Typhimurium infection of mice because it is a model of typhoid like disease in humans. We have organized effectors in terms of events that happen during the infection cycle and how secreted effectors may be involved.

  4. Dissecting soft radiation with factorization.

    PubMed

    Stewart, Iain W; Tackmann, Frank J; Waalewijn, Wouter J

    2015-03-01

    An essential part of high-energy hadronic collisions is the soft hadronic activity that underlies the primary hard interaction. It includes soft radiation from the primary hard partons, secondary multiple parton interactions (MPI), and factorization-violating effects. The invariant mass spectrum of the leading jet in Z+jet and H+jet events is directly sensitive to these effects, and we use a QCD factorization theorem to predict its dependence on the jet radius R, jet p_{T}, jet rapidity, and partonic process for both the perturbative and nonperturbative components of primary soft radiation. We prove that the nonperturbative contributions involve only odd powers of R, and the linear R term is universal for quark and gluon jets. The hadronization model in Pythia8 agrees well with these properties. The perturbative soft initial state radiation (ISR) has a contribution that depends on the jet area in the same way as the underlying event, but this degeneracy is broken by dependence on the jet p_{T}. The size of this soft ISR contribution is proportional to the color state of the initial partons, yielding the same positive contribution for gg→Hg and gq→Zq, but a negative interference contribution for qq[over ¯]→Zg. Hence, measuring these dependencies allows one to separate hadronization, soft ISR, and MPI contributions in the data. PMID:25793802

  5. Environmental factors in cardiovascular disease.

    PubMed

    Cosselman, Kristen E; Navas-Acien, Ana; Kaufman, Joel D

    2015-11-01

    Environmental exposure is an important but underappreciated risk factor contributing to the development and severity of cardiovascular disease (CVD). The heart and vascular system are highly vulnerable to a number of environmental agents--ambient air pollution and the metals arsenic, cadmium, and lead are widespread and the most-extensively studied. Like traditional risk factors, such as smoking and diabetes mellitus, these exposures advance disease and mortality via augmentation or initiation of pathophysiological processes associated with CVD, including blood-pressure control, carbohydrate and lipid metabolism, vascular function, and atherogenesis. Although residence in highly polluted areas is associated with high levels of cardiovascular risk, adverse effects on cardiovascular health also occur at exposure levels below current regulatory standards. Considering the widespread prevalence of exposure, even modest contributions to CVD risk can have a substantial effect on population health. Evidence-based clinical and public-health strategies aimed at reducing environmental exposures from current levels could substantially lower the burden of CVD-related death and disability worldwide. PMID:26461967

  6. Environmental factors influencing blackfly populations

    PubMed Central

    Carlsson, G.

    1967-01-01

    Much more information is required on the distribution of blackflies in various parts of the world, and in many cases an adequate methodology for obtaining such information still has to be worked out. A detailed methodology for the collection of information about blackflies is given, which was developed for investigations mainly in the Holarctic regions but is basically applicable to other parts of the world. A brief survey of the population dynamics of various species of blackflies in various parts of the Holarctic regions is given, and the main factors influencing the population dynamics are discussed. Interspecific and intraspecific fluctuations in natural blackfly populations are attributed chiefly to abiotic environmental factors rather than to competition. Larval competition in a given microhabitat is mainly individual, though specimens belonging to a given species may have a slightly more favourable position than others. The use of parasites and in particular the replacement of one species by another are promising methods of blackfly control. Predators are not generally likely to prove useful for this purpose. PMID:5300046

  7. Factors identified for negative appendicectomies.

    PubMed

    Mirza, M R; Habib, L; Jaleel, F

    2009-07-01

    The study was done, to determine the factors for negative appendicectomies. This prospective descriptive study includes patients managed at four non teaching and a teaching hospital of Karachi from March 2006 to February 2008. One hundred and sixty eight patients underwent appendicectomy during the study period. Details of clinical presentations, investigations, operative findings and histopathology were entered and analyzed. Literature search was aimed to see the negative appendicectomy rate (NAR) in last ten years despite using diagnostic tools (clinical scoring, diagnostic imaging and laparoscopy). In this study a total number of 168 patients under went appendicectomy. Normal appendices were found in 31 patients (negative appendicectomy rate was 18.45%) and associated pathology was seen in 13 patients, an incidental finding of Meckel's diverticulum in 5 patients and no other pathology was seen in 13 patients. The different factors which we identified for negative appendicectomies in our practice were non teaching hospitals where diagnostic scoring system was difficult to apply, female gender, selective use of imaging modality, other pathologies presenting with pain in right lower quadrant (RLQ) and requiring surgical intervention, and non-availability of CT scan and laparoscopy. Despite many advances in diagnostic system, acute appendicitis is still a diagnostic dilemma at times. Although there is no substitute for clinical judgment but in sub groups of patients in whom the possibility of negative appendicectomy is high, diagnostic modalities should be used judiciously to decrease the negative exploration. PMID:19623147

  8. Factors Affecting Aerosol Radiative Forcing

    NASA Astrophysics Data System (ADS)

    Wang, Jingxu; Lin, Jintai; Ni, Ruijing

    2016-04-01

    Rapid industrial and economic growth has meant a large amount of aerosols in the atmosphere with strong radiative forcing (RF) upon the climate system. Over parts of the globe, the negative forcing of aerosols has overcompensated for the positive forcing of greenhouse gases. Aerosol RF is determined by emissions and various chemical-transport-radiative processes in the atmosphere, a multi-factor problem whose individual contributors have not been well quantified. In this study, we analyze the major factors affecting RF of secondary inorganic aerosols (SIOAs, including sulfate, nitrate and ammonium), primary organic aerosol (POA), and black carbon (BC). We analyze the RF of aerosols produced by 11 major regions across the globe, including but not limited to East Asia, Southeast Asia, South Asia, North America, and Western Europe. Factors analyzed include population size, per capita gross domestic production (GDP), emission intensity (i.e., emissions per unit GDP), chemical efficiency (i.e., mass per unit emissions) and radiative efficiency (i.e., RF per unit mass). We find that among the 11 regions, East Asia produces the largest emissions and aerosol RF, due to relatively high emission intensity and a tremendous population size. South Asia produce the second largest RF of SIOA and BC and the highest RF of POA, in part due to its highest chemical efficiency among all regions. Although Southeast Asia also has large emissions, its aerosol RF is alleviated by its lowest chemical efficiency. The chemical efficiency and radiative efficiency of BC produced by the Middle East-North Africa are the highest across the regions, whereas its RF is lowered by a small per capita GDP. Both North America and Western Europe have low emission intensity, compensating for the effects on RF of large population sizes and per capita GDP. There has been a momentum to transfer industries to Southeast Asia and South Asia, and such transition is expected to continue in the coming years. The

  9. Form factors from lattice QCD

    SciTech Connect

    Dru Renner

    2012-04-01

    Precision computation of hadronic physics with lattice QCD is becoming feasible. The last decade has seen precent-level calculations of many simple properties of mesons, and the last few years have seen calculations of baryon masses, including the nucleon mass, accurate to a few percent. As computational power increases and algorithms advance, the precise calculation of a variety of more demanding hadronic properties will become realistic. With this in mind, I discuss the current lattice QCD calculations of generalized parton distributions with an emphasis on the prospects for well-controlled calculations for these observables as well. I will do this by way of several examples: the pion and nucleon form factors and moments of the nucleon parton and generalized-parton distributions.

  10. Cancer Treatment: The Cost Factor.

    PubMed

    Smith, S

    2014-12-01

    Countries in the Caribbean region have expressed concern at the rising incidence of chronic non-communicable diseases. Cancer is one of these and the cost of treating patients with this has escalated in the recent past. In this paper, the author examines colon cancer and the cost of caring for patients with this. A viewpoint with regard to the reasons for the increased cost of care of patients with cancer is advanced. The factors contributing to the increasing costs are explored. Research epistemology and the role of the pharmaceutical industry are also explored. The need for consensus decision-making with regard to choice of agent/regime is emphasized, as is the need for a deliberate cost-benefit approach. PMID:25867563

  11. Trends in human factors research.

    PubMed

    Cohen, A

    1982-06-01

    As just described, NIOSH's ongoing and new activities offer varied approaches and opportunities for gaining insights into human factor and ergonomic aspects of workplace hazards and their control. They represent a blend of surveillance work (re, the prevalence survey of chronic trauma risk), in-depth studies of known workplace problems emphasizing undue physical and psychological job demands and their consequences (re, stress from machine-paced work and musculoskeletal problems from repeated lifting), first evaluations of the consequences of new technology (re, use of video display terminals), and finally problem-solving efforts (re, the evaluation and field testing of the work practice guide for reducing lifting hazards and control technology assessment). Taken together, these efforts signal an important new commitment by NIOSH in making workplaces safe for our working men and women. PMID:6896907

  12. Factors that characterize street injectors.

    PubMed

    Klee, H; Morris, J

    1995-06-01

    Injecting drugs in the streets and other public places is increasingly common in many cities and large towns in the United Kingdom. It is a practice rarely open to view, but the evidence is there in the used needles and syringes left in stairwells of flats, shop doorways, public toilets and other areas where exposure can be avoided. Although it is a development with serious implications for public health, it has received little research attention. This paper reports the factors associated with street injecting from 56 polydrug users who regularly injected in public places. It reveals that they were more likely to be severely drug dependent with associated health problems. A high proportion were homeless. Their drug-related and sexual risk behaviour have implications for the acquisition and transmission of disease. PMID:7633302

  13. Occupational factors and pancreatic cancer.

    PubMed

    Norell, S; Ahlbom, A; Olin, R; Erwald, R; Jacobson, G; Lindberg-Navier, I; Wiechel, K L

    1986-11-01

    The relation between occupational factors and pancreatic cancer has been studied by two different approaches: a population based case-control study with two series of controls and a retrospective cohort study based on register data. With both approaches, some support was found for an association with occupational exposure to petroleum products. Associations were also indicated with exposure to paint thinner (case-control study) and work in painting and in paint and varnish factories (cohort study), for exposure to detergents, floor cleaning agents, or polish (case-control study) and with floor polishing or window cleaning (cohort study), and for exposure to refuse (case-control study) and work in refuse disposal plants (cohort study). PMID:3790458

  14. Environmental factors in helicopter operations.

    PubMed

    Thornton, R; Vyrnwy-Jones, P

    1984-10-01

    The environmental problems affecting aircrew are partly those which all soldiers face, such as noise, heat and cold, and partly peculiar to the medium and the vehicle in which aircrew train and fight, such as disorientation and decompression. The cockpit environment of the modern helicopter is luxurious in comparison with many of its predecessors, yet most of the adverse effects of flight on the man still pertain. The result can, predictably, be acute and disastrous, resulting in an accident produced by severe disorientation, or chronic, producing insidious fatigue and performance decrement, which may also result in an accident. One particular stressor may be dominant in a given situation, but generally, many separate factors act simultaneously to produce their results. PMID:6527345

  15. The main Aeromonas pathogenic factors.

    PubMed

    Tomás, J M

    2012-01-01

    The members of the Aeromonas genus are ubiquitous, water-borne bacteria. They have been isolated from marine waters, rivers, lakes, swamps, sediments, chlorine water, water distribution systems, drinking water and residual waters; different types of food, such as meat, fish, seafood, vegetables, and processed foods. Aeromonas strains are predominantly pathogenic to poikilothermic animals, and the mesophilic strains are emerging as important pathogens in humans, causing a variety of extraintestinal and systemic infections as well as gastrointestinal infections. The most commonly described disease caused by Aeromonas is the gastroenteritis; however, no adequate animal model is available to reproduce this illness caused by Aeromonas. The main pathogenic factors associated with Aeromonas are: surface polysaccharides (capsule, lipopolysaccharide, and glucan), S-layers, iron-binding systems, exotoxins and extracellular enzymes, secretion systems, fimbriae and other nonfilamentous adhesins, motility and flagella. PMID:23724321

  16. Reliability factors in gas lasers

    NASA Astrophysics Data System (ADS)

    Malk, E. G.; Ramsay, I. A.

    1982-07-01

    Two types of gas lasers, the helium-neon laser and the sealed off, waveguide carbon dioxide laser, are discussed. The beneficial influence of hard seals on the HeNe laser is briefly described, and the resulting improved mean time between failures is described and discussed, showing a summary of lifetest data. Rejection percentages at 80 percent of the rated power in 18 months of elapsed time is determined to be 10 percent for one family of HeNe lasers and 7.6 percent for another family. An optical failure mode for HeNe lasers and the scientific investigation leading to its elimination are described. Finally, CO2 waveguide laser reliability is discussed in terms of the lifetime degradation factors involved in the operation of these lasers.

  17. Manned Mars mission crew factors

    NASA Technical Reports Server (NTRS)

    Santy, Patricia A.

    1986-01-01

    Crew factors include a wide range of concerns relating to the human system and its role in a Mars mission. There are two important areas which will play a large part in determining the crew for a Mars mission. The first relates to the goals and priorities determined for such a vast endeavor. The second is the design of the vehicle for the journey. The human system cannot be separated from the other systems in that vehicle. In fact it will be the human system which drives the development of many of the technical breakthroughs necessary to make a Mars mission successful. As much as possible, the engineering systems must adapt to the needs of the human system and its individual components.

  18. Factors affecting rotator cuff healing.

    PubMed

    Mall, Nathan A; Tanaka, Miho J; Choi, Luke S; Paletta, George A

    2014-05-01

    Several studies have noted that increasing age is a significant factor for diminished rotator cuff healing, while biomechanical studies have suggested the reason for this may be an inferior healing environment in older patients. Larger tears and fatty infiltration or atrophy negatively affect rotator cuff healing. Arthroscopic rotator cuff repair, double-row repairs, performing a concomitant acromioplasty, and the use of platelet-rich plasma (PRP) do not demonstrate an improvement in structural healing over mini-open rotator cuff repairs, single-row repairs, not performing an acromioplasty, or not using PRP. There is conflicting evidence to support postoperative rehabilitation protocols using early motion over immobilization following rotator cuff repair. PMID:24806015

  19. Psychosocial factors in Parkinson's disease.

    PubMed

    MacCarthy, B; Brown, R

    1989-02-01

    Self-report measures were administered to 136 patients with Parkinson's disease in order to explore the relationships between aspects of psychological adjustment (depression, positive affect and acceptance of illness) and physical illness (duration of the illness, stage of illness and functional disability). Many psychosocial variables which, it was hypothesized, might intervene in the relationship between physical and psychological status were also measured. These were coping style, social support, self-esteem, attributions about the onset and course of the illness, perceived control and previous psychiatric history. A variable pattern of relationships between the different indices of psychological adjustment and physical illness emerged. Self-esteem, coping style and practical support contributed significantly to the variance in psychological adjustment. It was concluded that well-being in Parkinsonian patients is not exclusively dependent on a simple relationship between disability and depression, and that other factors should be taken into account in the clinical management of the illness. PMID:2924026

  20. Cancer Treatment: The Cost Factor

    PubMed Central

    Smith, S

    2014-01-01

    ABSTRACT Countries in the Caribbean region have expressed concern at the rising incidence of chronic non-communicable diseases. Cancer is one of these and the cost of treating patients with this has escalated in the recent past. In this paper, the author examines colon cancer and the cost of caring for patients with this. A viewpoint with regard to the reasons for the increased cost of care of patients with cancer is advanced. The factors contributing to the increasing costs are explored. Research epistemology and the role of the pharmaceutical industry are also explored. The need for consensus decision-making with regard to choice of agent/regime is emphasized, as is the need for a deliberate cost-benefit approach. PMID:25867563