bluuebunny/crossref_metadata_2025 huggingface dataset:
Milk Fat Globule Epidermal Growth Factor-Factor VIII Is Down-Regulated in Sepsis via the Lipopolysaccharide-CD14 Pathway
Authors: Komura Hidefumi , Miksa Michael , Wu Rongqian , Goyert Sanna M. , Wang Ping
Published: April 2014

Phagocytosis prevents the release of potentially harmful or immunogenic materials from dying cells. Milk fat globule epidermal growth factor (EGF)-factor VIII (MFG-E8) mediates the clearance of apoptotic cells. We have previously shown that the administration of MFG-E8-rich exosomes from immature dendritic cells promotes the phagocytosis of apoptotic cells and improves survival in sepsis. Because endotoxin is elevated in polymicrobial sepsis, we hypothesized that down-regulation of MFG-E8 is mediated via the LPS-CD14 pathway, eventually leading to the accruement of apoptotic cells. Polymicrobial sepsis was induced by cecal ligation and puncture (CLP) in CD14-deficient (CD14−/−), TLR4-mutated and wild-type (WT) mice. In addition, endotoxemia was elicited by i.p. injection of LPS. LPS was also neutralized by pretreating CLP-induced WT mice with polymyxin B. Splenic MFG-E8 expression, phagocytic activity, and apoptosis were assessed 5 and 20 h after CLP or 5 h after LPS administration. In septic WT mice, MFG-E8 mRNA and protein levels were suppressed by 49 and 33%, respectively. Endotoxemia reduced MFG-E8 mRNA expression in a dose dependent manner and the down-regulation of MFG-E8 mRNA expression in CLP-induced sepsis was attenuated by polymyxin B. This CLP-induced suppression was not observed in both CD14−/− and TLR4-mutated mice. CLP significantly decreased phagocytic activity of peritoneal macrophages in WT (by 30%), but not in CD14−/− mice. CLP also induced significant apoptosis in the spleen of WT (by 61%), but less in CD14−/− mice. Thus, MFG-E8 production is down-regulated in sepsis by LPS-CD14 dependent fashion, leading to a reduction of phagocytosis of apoptotic cells.
Potential Roles of a Special CD8αα+ Cell Population and CC Chemokine Thymus-Expressed Chemokine in Ovulation Related Inflammation
Authors: Zhou Cindy , Wu Jean , Borillo Jason , Torres Lisa , McMahon John , Lou Ya-Huan
Published: April 2014

It is well known that ovulation may be an inflammatory process. However, it remains elusive how immune cells participate in this process. We have identified a novel CD8αα+ population, which resembles tissue dendritic cells, in the theca of antral follicles. We further observed a dramatic influx of the CD8αα+cells into the ovulating follicles. This CD8αα+population was absent in the ovary of estradiol-induced anovulatory C31F1 mice and subfertile athymic nude mice. Expression of a CC chemokine thymus-expressed chemokine (TECK) has previously been found in the ovary; we further demonstrated that TECK attracted CD8αα+cells into the ovary. Anti-TECK Ab, elicited in the female mice by active immunization, depleted the ovarian CD8αα+ cells in vivo. Mice with a high titer of TECK Ab failed to ovulate after superovulation induction. More importantly, the immunized mice had greatly reduced fertility, which was positively correlated with the Ab titers. Ovarian TECK expression was normal in anovulatory C31F1 mice, suggesting that infertility in the immunized mice is due to a block of CD8αα+ cell migration. Finally, the origin of ovarian CD8αα+ cells was explored. Upon being transferred, thymic CD8α+ cells were able to home to the theca of follicles in the recipients. Thus, ovarian CD8αα+ cells, which participate in the ovulation-related inflammation, may originate in the thymus.
CD11b+ Myeloid Cells Are the Key Mediators of Th2 Cell Homing into the Airway in Allergic Inflammation
Authors: Medoff Benjamin D. , Seung Edward , Hong Sandra , Thomas Seddon Y. , Sandall Barry P. , Duffield Jeremy S. , Kuperman Douglas A. , Erle David J. , Luster Andrew D.
Published: April 2014

STAT6-mediated chemokine production in the lung is required for Th2 lymphocyte and eosinophil homing into the airways in allergic pulmonary inflammation, and thus is a potential therapeutic target in asthma. However, the critical cellular source of STAT6-mediated chemokine production has not been defined. In this study, we demonstrate that STAT6 in bone marrow-derived myeloid cells was sufficient for the production of CCL17, CCL22, CCL11, and CCL24 and for Th2 lymphocyte and eosinophil recruitment into the allergic airway. In contrast, STAT6 in airway-lining cells did not mediate chemokine production or support cellular recruitment. Selective depletion of CD11b+ myeloid cells in the lung identified these cells as the critical cellular source for the chemokines CCL17 and CCL22. These data reveal that CD11b+ myeloid cells in the lung help orchestrate the adaptive immune response in asthma, in part, through the production of STAT6-inducible chemokines and the recruitment of Th2 lymphocytes into the airway.
Th17-Polarized Immune Response in a Murine Model of Hypersensitivity Pneumonitis and Lung Fibrosis
Authors: Simonian Philip L. , Roark Christina L. , Wehrmann Fabian , Lanham Allison K. , Diaz del Valle Fernando , Born Willi K. , O’Brien Rebecca L. , Fontenot Andrew P.
Published: April 2014

Hypersensitivity pneumonitis is an environmental lung disease characterized by a diffuse mononuclear cell infiltrate in the lung that can progress to pulmonary fibrosis with chronic exposure to an inhaled Ag. Using a well-established murine model of hypersensitivity pneumonitis, we repeatedly exposed C57BL/6 mice to Saccharopolyspora rectivirgula to investigate whether T cells are required for lung fibrosis. In the absence of αβ T cells, TCRβ−/− mice exposed to S. rectivirgula for 4 wk had markedly decreased mononuclear infiltrates and collagen deposition in the lung compared with wild-type C57BL/6 mice. In contrast to CD8+ T cells, adoptive transfer of CD4+ T cells reconstituted the S. rectivirgula-induced inflammatory and fibrotic response, suggesting that the CD4+ T cell represents the critical αβ T cell subset. Cytokine analysis of lung homogenates at various time points after S. rectivirgula exposure failed to identify a predominant Th1 or Th2 phenotype. Conversely, IL-17 was found in the lung at increasing concentrations with continued exposure to S. rectivirgula. Intracellular cytokine staining revealed that 14% of CD4+ T cells from the lung of mice treated with S. rectivirgula expressed IL-17A. In the absence of IL-17 receptor signaling, Il17ra−/− mice had significantly decreased lung inflammation and fibrosis compared with wild-type C57BL/6 mice. These data are the first to demonstrate an important role for Th17-polarized CD4+ T lymphocytes in the immune response directed against S. rectivirgula in this murine model of hypersensitivity pneumonitis and pulmonary fibrosis.
JNK MAPK Pathway Regulates Constitutive Transcription of CCL5 by Human NK Cells through SP1
Authors: Kumar Dilip , Hosse Judith , von Toerne Christine , Noessner Elfriede , Nelson Peter J.
Published: April 2014

The MAPKs ERK, JNK, and p38 control diverse aspects of the immune response, including regulation of cytotoxin biology in NK cells and CTL. The chemokine CCL5 is coreleased with the cytotoxins, perforin, the granzymes, and granulysin, during the lethal hit administered by cytotoxic CD8+ T cells (CTL). CCL5 expression is up-regulated relatively late in CTL coincident with their functional maturation 3–7 days after activation. Unlike T cells, NK cells have the ability to kill virally infected or transformed cells when directly isolated from the peripheral circulation. In this study, we show that in contrast to T cells, peripheral blood NK cells express CCL5 constitutively. The use of specific inhibitors of the JNK, ERK, and p38 MAPK pathways showed that the JNK pathway controls expression of CCL5 by NK cells. Promoter-reporter assays identified a compact region of the CCL5 promoter responsible for the constitutive transcription of CCL5 by NK cells. EMSA, chromatin immune precipitation, the use of heterologous promoters, and site-directed mutagenesis demonstrated that transcription in NK cells is largely controlled through binding of the transcription factor specificity protein 1 to a region −75 to −56 upstream of the site of transcriptional initiation. Specificity protein 1 expression, and in turn the constitutive expression of CCL5, was found to be controlled through constitutive activation of the JNK/MAPK pathway in peripheral blood NK cells.
Regulation of the foxp3 Gene by the Th1 Cytokines: The Role of IL-27-Induced STAT1
Authors: Ouaked Nadia , Mantel Pierre-Yves , Bassin Claudio , Burgler Simone , Siegmund Kerstin , Akdis Cezmi A. , Schmidt-Weber Carsten B.
Published: April 2014

Impaired functional activity of T regulatory cells has been reported in allergic patients and results in an increased susceptibility to autoimmune diseases. The master regulator of T regulatory cell differentiation, the transcription factor FOXP3, is required for both their development and function. Despite its key role, relatively little is known about the molecular mechanisms regulating foxp3 gene expression. In the present study, the effect of Th1 cytokines on human T regulatory cell differentiation was analyzed at epigenetic and gene expression levels and reveals a mechanism by which the STAT1-activating cytokines IL-27 and IFN-γ amplify TGF-β-induced FOXP3 expression. This study shows STAT1 binding elements within the proximal part of the human FOXP3 promoter, which we previously hypothesized to function as a key regulatory unit. Direct binding of STAT1 to the FOXP3 promoter following IL-27 stimulation increases its transactivation process and induces permissive histone modifications in this key region of the FOXP3 promoter, suggesting that FOXP3 expression is promoted by IL-27 by two mechanisms. Our data demonstrate a molecular mechanism regulating FOXP3 expression, which is of considerable interest for the development of new drug targets aiming to support anti-inflammatory mechanisms of the immune system.
Pulmonary Vγ4+ γδ T Cells Have Proinflammatory and Antiviral Effects in Viral Lung Disease
Authors: Dodd Jonathan , Riffault Sabine , Kodituwakku Jayanie S. , Hayday Adrian C. , Openshaw Peter J. M.
Published: April 2014

Host defenses, while effecting viral clearance, contribute substantially to inflammation and disease. This double action is a substantial obstacle to the development of safe and effective vaccines against many agents, particularly respiratory syncytial virus (RSV). RSV is a common cold virus and the major cause of infantile bronchiolitis worldwide. The role of αβ T cells in RSV-driven immunopathology is well studied, but little is known about the role of “unconventional” T cells. During primary RSV challenge of BALB/c mice, some Vγ7+ γδ T cells were present; however, immunization with a live vaccinia vector expressing RSV F protein substantially enhanced Vγ4+ γδ T cell influx after RSV infection. Harvested early, these cells produced IFN-γ, TNF, and RANTES after ex vivo stimulation. By contrast, those recruited 5 days after challenge made IL-4, IL-5, and IL-10. Depletion of γδ T cells in vivo reduced lung inflammation and disease severity and slightly increased peak viral replication but did not prevent viral clearance. These studies demonstrate a novel role for γδ T cells in the development of immunopathology and cellular influx into the lungs after immunization and RSV challenge. Though a minor population, γδ T cells have a critical influence on disease and are an attractive interventional target in the alleviation of viral lung disease.
Rapid Degranulation of NK Cells following Activation by HIV-Specific Antibodies
Authors: Chung Amy W. , Rollman Erik , Center Rob J. , Kent Stephen J. , Stratov Ivan
Published: April 2014

Ab-dependent cellular cytotoxicity (ADCC) Abs stimulate NK cell effector functions and play a role in protecting from and controlling viral infections. We characterized ADCC Abs in a cross-sectional cohort of 80 HIV-infected subjects not on antiretroviral therapy. We analyzed ADCC response by killing fluorescently labeled target cells, as well as expression of IFN-γ and the degranulation marker CD107a from activated NK cells as measured by a novel intracellular cytokine assay. HIV-specific ADCC directed toward Envelope proteins were present in the majority of 80 untreated HIV-infected individuals measured by killing function. Similarly, most subjects had HIV-specific Abs that mediated degranulation or cytokine expression by NK cells. Interestingly, there was a poor correlation between ADCC-mediated killing of fluorescently labeled whole Envelope protein-pulsed cell lines and Ab-mediated expression of IFN-γ by NK cells. However, in contrast to healthy donor NK cells, autologous patient NK cells more effectively degranulated granzyme B in response to ADCC activation. Activation of NK cells in response to stimulation by HIV-specific Abs occurs at least as rapidly as activation of Gag-specific CTLs. Our studies highlight the complexity of ab-mediated NK cell activation in HIV infection, and suggest new avenues toward studying the utility of ADCC in controlling HIV infection.
Attenuated Expression of A20 Markedly Increases the Efficacy of Double-Stranded RNA-Activated Dendritic Cells As an Anti-Cancer Vaccine
Authors: Breckpot Karine , Aerts-Toegaert Cindy , Heirman Carlo , Peeters Uschi , Beyaert Rudi , Aerts Joeri L. , Thielemans Kris
Published: April 2014

A20 is a zinc finger protein with ubiquitin-modifying activity. A20 has been described as negatively regulating signaling induced by the TNF receptor and TLR family in a number of cell types, including mouse bone marrow-derived dendritic cells (DCs). However, the expression and effect of A20 in activated human monocyte-derived DCs have not been previously evaluated. We report that DCs activated with the TLR3 ligand poly(I:C) up-regulate A20. Down-regulating A20 demonstrated its role in the functional activation of DCs. A20 down-regulated DCs showed higher activation of the transcription factors NF-κB and activator protein-1, which resulted in increased and sustained production of IL-6, IL-10, and IL-12p70. We additionally silenced the immunosuppressive cytokine IL-10 and demonstrated that IL-10 inhibits T cell proliferation. We further demonstrated that A20 down-regulated DCs skew naive CD4+ T cells toward IFN-γ producing Th1 cells, a process which is dependent on IL-12p70 and which is unaffected by IL-10. Furthermore, A20 and/or IL-10 down-regulated DCs had an enhanced capacity to prime Melan-A/MART-1 specific CD8+ T cells. Finally, we demonstrated that potent T cell stimulatory DCs are generated by the simultaneous delivery of poly(I:C12U), A20, or A20/IL-10 small interfering RNA and Ag-encoding mRNA, introducing a one step approach to improve DC-based vaccines. Together these findings demonstrate that A20 negatively regulates NF-κB and activator protein-1 in DCs and that down-regulation of A20 results in DCs with enhanced T cell stimulatory capacity.
Endogenous 4-1BB Ligand Plays a Critical Role in Protection from Influenza-Induced Disease
Authors: Lin Gloria H. Y. , Sedgmen Bradley J. , Moraes Theo J. , Snell Laura M. , Topham David J. , Watts Tania H.
Published: April 2014

A critical issue during severe respiratory infection is whether it is the virus or the host response that does the most damage. In this study, we show that endogenous 4-1BBL plays a critical role in protecting mice from severe effects of influenza disease. During mild respiratory influenza infection in which virus is rapidly cleared, the inducible costimulatory receptor 4-1BB is only transiently induced on lung T cells and 4-1BB ligand (4-1BBL) is completely dispensable for the initial CD8 T cell response and mouse survival. In contrast, during more severe respiratory influenza infection with prolonged viral load, 4-1BB expression on lung CD8 T cells is sustained, and 4-1BBL-deficient mice show decreased CD8 T cell accumulation in the lungs, decreased viral clearance, impaired lung function, and increased mortality. Transfer of an optimal number of naive Ag-specific T cells before infection protects wild-type but not 4-1BBL-deficient mice from an otherwise lethal dose of influenza virus. Transfer of T cells lacking the proapoptotic molecule Bim extends the lifespan of 4-1BBL-deficient mice by one to three days, suggesting that at least part of the role of 4-1BB/4-1BBL is to prolong effector cell survival long enough to clear virus. Intranasal delivery of 4-1BBL by recombinant adenovirus marginally improves survival of 4-1BBL-deficient mice at low dose, but exacerbates disease at high dose. These findings suggest a rationale for the evolutionary accumulation of inducible costimulatory molecules, thereby allowing the immune system to sustain the expression of molecules such as 4-1BB to a level commensurate with severity of infection.
A Dual Role for Talin in NK Cell Cytotoxicity: Activation of LFA-1-Mediated Cell Adhesion and Polarization of NK Cells
Authors: Mace Emily M. , Monkley Susan J. , Critchley David R. , Takei Fumio
Published: April 2014

LFA-1 is critical for NK cell cytotoxicity because it mediates adhesion of NK cells to target cells. Talin is thought to associate with the cytoplasmic tail of LFA-1 and activates its ligand-binding function. In this study, we report that talin is also required for LFA-1-mediated outside-in signaling leading to NK cell polarization. NK cells generated from talin1-deficient murine embryonic stem cells are defective in LFA-1-mediated adhesion. Although exogenously added manganese activates LFA-1 on talin-deficient NK cells and induces conjugate formation with target cells, their LFA-1-dependent cytotoxicity is impaired. Binding of ICAM-1-coated beads to wild-type NK cells induces reorganization of the actin cytoskeleton and coligation of the activating receptor NKG2D induces polarization of cytotoxic granules, whereas talin1-deficient NK cells fail to polarize with or without NKG2D coligation. Thus, talin1 plays a dual role in NK cell cytotoxicity, first by activation of LFA-1-mediated adhesion and then via LFA-1-induced NK cell polarization.
Lymphopenia-Induced Proliferation Is a Potent Activator for CD4+ T Cell-Mediated Autoimmune Disease in the Retina
Authors: McPherson Scott W. , Heuss Neal D. , Gregerson Dale S.
Published: April 2014

To study retinal immunity in a defined system, a CD4+ TCR transgenic mouse line (βgalTCR) specific for β-galactosidase (βgal) was created and used with transgenic mice that expressed βgal in retinal photoreceptor cells (arrβgal mice). Adoptive transfer of resting βgalTCR T cells, whether naive or Ag-experienced, into arrβgal mice did not induce retinal autoimmune disease (experimental autoimmune uveoretinitis, EAU) and gave no evidence of Ag recognition. Generation of βgalTCR T cells in arrβgal mice by use of bone marrow grafts, or double-transgenic mice, also gave no retinal disease or signs of Ag recognition. Arrβgal mice were also resistant to EAU induction by adoptive transfer of in vitro-activated βgalTCR T cells, even though the T cells were pathogenic if the βgal was expressed elsewhere. In vitro manipulations to increase T cell pathogenicity before transfer did not result in EAU. The only strategy that induced a high frequency of severe EAU was transfer of naive, CD25-depleted, βgalTCR T cells into lymphopenic arrβgal recipients, implicating regulatory T cells in the T cell inoculum, as well as in the recipients, in the resistance to EAU. Surprisingly, activation of the CD25-depleted βgalTCR T cells before transfer into the lymphopenic recipients reduced EAU. Taken together, the results suggest that endogenous regulatory mechanisms, as well as peripheral induction of regulatory T cells, play a role in the protection from EAU.
PD-1 Blockade in Rhesus Macaques: Impact on Chronic Infection and Prophylactic Vaccination
Authors: Finnefrock Adam C. , Tang Aimin , Li Fengsheng , Freed Daniel C. , Feng Meizhen , Cox Kara S. , Sykes Kara J. , Guare James P. , Miller Michael D. , Olsen David B. , Hazuda Daria J. , Shiver John W. , Casimiro Danilo R. , Fu Tong-Ming
Published: April 2014

Programmed Cell Death 1 (PD-1) plays a crucial role in immunomodulation. Binding of PD-1 to its ligand receptors down-regulates immune responses, and published reports suggest that this immune modulation is exploited in cases of tumor progression or chronic viral infection to evade immune surveillance. Thus, blockade of this signal could restore or enhance host immune functions. To test this hypothesis, we generated a panel of mAbs specific to human PD-1 that block PD ligand 1 and tested them for in vitro binding, blocking, and functional T cell responses, and evaluated a lead candidate in two in vivo rhesus macaque (Macaca mulatta) models. In the first therapeutic model, chronically SIV-infected macaques were treated with a single infusion of anti-PD-1 mAb; viral loads increased transiently before returning to, or falling below, pretreatment baselines. In the second prophylactic model, naive macaques were immunized with an SIV-gag adenovirus vector vaccine. Induced PD-1 blockade caused a statistically significant (p < 0.05) increase in the peak percentage of T cells specific for the CM9 Gag epitope. These new results on PD-1 blockade in nonhuman primates point to a broader role for PD-1 immunomodulation and to potential applications in humans.
Potential Contribution of IL-7 to Allergen-Induced Eosinophilic Airway Inflammation in Asthma
Authors: Kelly Elizabeth A. B. , Koziol-White Cynthia J. , Clay Kathryn J. , Liu Lin Ying , Bates Mary Ellen , Bertics Paul J. , Jarjour Nizar N.
Published: April 2014

The primary function of IL-7 is to promote maturation and survival of T cells. Through microarray expression analysis, we previously observed that human blood eosinophils express mRNA for IL-7Rα (CD127) and its common γ chain (CD132). The purpose of this study was to determine whether eosinophils have functional IL-7 receptors and to assess the potential contribution of IL-7 to eosinophilic airway inflammation by evaluating its presence in bronchoalveolar lavage (BAL) fluid of subjects with atopic asthma before and after segmental bronchoprovocation with allergen. Immunoblot analysis revealed that CD127 is present in highly purified human blood eosinophils. Furthermore, eosinophils responded to IL-7 with phosphorylation of STAT5, up-regulation of the activation marker CD69, and prolonged survival. Neutralization of GM-CSF but not IL-5 significantly blunted these functional responses, suggesting that IL-7 mediates its effects by promoting eosinophil release of autologous GM-CSF. Notably, the suppressive effect of anti-GM-CSF on STAT5 phosphorylation occurred within 10 min of eosinophil exposure to IL-7. Thus, IL-7 likely activates eosinophil release of preformed rather than newly synthesized GM-CSF. The biological relevance of IL-7 to eosinophilia in vivo was implicated in a study of airway allergen challenge in patients with allergic asthma. IL-7 concentrations in BAL fluid increased significantly 48 h after segmental allergen challenge and were highly correlated with BAL eosinophils (r = 0.7, p < 0.001). In conclusion, the airway response to allergen is associated with the generation of IL-7, which may contribute to airway inflammation by promoting enhanced eosinophil activation and survival. Activation of eosinophils is a novel function for IL-7.
Distinct and Overlapping Patterns of Cytokine Regulation of Thymic and Bone Marrow-Derived NK Cell Development
Authors: Cheng Min , Charoudeh Hojjatollah Nozad , Brodin Petter , Tang Yanjuan , Lakshmikanth Tadepally , Höglund Petter , Jacobsen Sten Eirik W. , Sitnicka Ewa
Published: April 2014

Although bone marrow (BM) represents the main site for postnatal NK cell development, recently a distinct thymic-dependent NK cell pathway was identified. These studies were designed to investigate the role of cytokines in regulation of thymic NK cells and to compare with established regulatory pathways of BM-dependent NK cell compartment. The common cytokine receptor γ-chain (Il2rg) essential for IL-15-induced signaling, and FMS-like tyrosine kinase 3 (FLT3) receptor ligand (Flt3l) were previously identified as important regulatory pathways of the BM NK cell compartment based on lack of function studies in mice, however their complementary action remains unknown. By investigating mice double-deficient in Il2rg and Flt3l (Flt3l−/− Il2rg−/−), we demonstrate that FLT3L is important for IL2Rg-independent maintenance of both immature BM as well as peripheral NK cells. In contrast to IL-7, which is dispensable for BM but important for thymic NK cells, IL-15 has a direct and important role in both thymic and BM NK cell compartments. Although thymic NK cells were not affected in Flt3l−/− mice, Flt3l−/−Il2rg−/− mice lacked detectable thymic NK cells, suggesting that FLT3L is also important for IL-2Rg-independent maintenance of thymic NK cells. Thus, IL-2Rg cytokines and FLT3L play complementary roles and are indispensable for homeostasis of both BM and thymic dependent NK cell development, suggesting that the cytokine pathways crucial for these two distinct NK cell pathways are largely overlapping.
OX40-Enhanced Tumor Rejection and Effector T Cell Differentiation Decreases with Age
Authors: Ruby Carl E. , Weinberg Andrew D.
Published: April 2014

OX40 agonists have potent immunotherapeutic effects against a variety of murine tumors, yet it is unclear the role that age-related immune senescence plays on their efficacy. We found that middle-aged and elderly tumor-bearing mice (12 and 20 mo old, respectively) treated with anti-OX40 were less responsive compared with young mice 6 mo or less of age. Decreased tumor-free survival was observed in both male and female mice, and was not due to changes in the surface expression of OX40 on T cells in older animals. Enumeration of cytokine-producing effector T cells in tumor-bearing mice revealed a significant decline in these cells in the older mice treated with anti-OX40 compared with their younger counterparts. The decrease of this critical T cell population in middle-aged mice was not a result of inherent T cell deficiencies, but was revealed to be T cell extrinsic. Finally, combining IL-12, an innate cytokine, with anti-OX40 boosted levels of differentiated effector T cells in the older anti-OX40-treated mice and partially restored the defective antitumor responses in the middle-aged mice. Our data show that the anti-OX40-enhancement of tumor immunity and effector T cell numbers is decreased in middle-aged mice and was partially reversed by coadministration of the proinflammatory cytokine IL-12.
Gene Expression Patterns Induced by HPV-16 L1 Virus-Like Particles in Leukocytes from Vaccine Recipients
Authors: García-Piñeres Alfonso J. , Hildesheim Allan , Dodd Lori , Kemp Troy J. , Yang Jun , Fullmer Brandie , Harro Clayton , Lowy Douglas R. , Lempicki Richard A. , Pinto Ligia A.
Published: April 2014

Human papillomavirus (HPV) virus-like particle (VLP) vaccines were recently licensed. Although neutralizing Ab titers are thought to be the main effectors of protection against infection, early predictors of long-term efficacy are not yet defined and a comprehensive understanding of innate and adaptive immune responses to vaccination is still lacking. Here, microarrays were used to compare the gene expression signature in HPV-16 L1 VLP-stimulated PBMCs from 17 vaccine and 4 placebo recipients before vaccination and 1 mo after receiving the second immunization. Vaccination with a monovalent HPV-16 L1 VLP vaccine was associated with modulation of genes involved in the inflammatory/defense response, cytokine, IFN, and cell cycle pathways in VLP-stimulated PBMCs. Additionally, there was up-regulation of probesets associated with cytotoxic (GZMB, TNFSF10) and regulatory (INDO, CTLA4) activities. The strongest correlations with neutralizing Ab titers were found for cyclin D2 (CCND2) and galectin (LGALS2). Twenty-two differentially expressed probesets were selected for confirmation by RT-PCR in an independent sample set. Agreement with microarray data was seen for more than two-thirds of these probesets. Up-regulation of immune/defense response genes by HPV-16 L1 VLP, in particular, IFN-induced genes, was observed in PBMCs collected before vaccination, with many of these genes being further induced following vaccination. In conclusion, we identified important innate and adaptive response-related genes induced by vaccination with HPV-16 L1 VLP. Further studies are needed to identify gene expression signatures of immunogenicity and long-term protection with potential utility in prediction of long-term HPV vaccination outcomes in clinical trials.
Bernlef en De Coninck
Authors: Kalla Irena Barbara
Published: April 2014

While the word ‘house’ was frequently used by the poets of the nineteen fifties, it was much less often used in the works of the poets of the next generation. However, it does not mean that this, very real, object plays no role in their poetry which was programmatically connected with reality. To illustrate this role, in this article there are two poems discussed (‘Je truitjes...’ by Herman de Coninck and ‘Juffrouw Van Leeuwen’ by Bernlef) where the word ‘house’ does not appear. Different aspects of the house understood as space are associated with the poetics of the Zestigers. In the analyses there is attention paid to the use of concepts. Both metaphoric and metonymic language use in cognitive linguistics is related to the embodied mind thesis – a belief that each thought is grounded in the bodily experience. The concept of ‘a poem’ in the analyses is associated with the concept of ‘a house.’ It is furthermore proved that carnality is also for the Zestigers the most important source of poetry. While the Vijftigers used the word ‘house’ metaphorically to show the connection between this subject and reality, in the neo-realistic poetry of the Zestigers the concept of ‘a house’ is referred to through the metonymic use of language.
Omwegen naar de literatuur - Kroniek van de literatuurwetenschap
Authors: Vervaeck Bart
Published: April 2014

Over de literatuur wordt zelden of nooit op een literaire manier geschreven. In de jaren zestig zei Tzvetan Todorov al dat je nooit trouw kon zijn aan een tekst – tenzij door hem letterlijk te kopiëren – en dat elke vorm van literatuurstudie per definitie de literaire tekst geweld aandoet. Algemener kun je volgens de (post)structuralisten nooit over A praten in termen van A. Je hebt een omweg nodig. Dat kan bijvoorbeeld de sociologie zijn, de filosofie of de psychoanalyse. Ik bespreek enkele omwegen aan de hand van enkele recente publicaties.
Modale partikels in het Nederlands als tweede taal: aanwijzingen voor een vaste verwervingsvolgorde1
Authors: van Balen Erna , Caspers Johanneke , van der Wouden Ton
Published: April 2014

On the basis of earlier research, it is likely that learners of Dutch as a second language (DSL) will have problems in acquiring modal particles, as these lexical items often have no direct counterparts in other languages. This hypothesis was tested by examining the spontaneous speech of six DSL-speakers with Spanish as their first language, and varied commands of Dutch. The results indicate that the speakers do use modal particles, but not in the same amounts: the higher the proficiency in Dutch, the larger the frequency and inventory of modal particles used. Furthermore, the particles seem to appear in a more or less fixed order.
Nederlandse partikelbeschrijving in internationaal perspectief: waar zijn we eigenlijk en waar moet het toch naar toe?
Authors: van der Wouden Ton , Caspers Johanneke
Published: April 2014

This final paper sketches the current state of knowledge with respect to the Dutch particles from an extramural perspective. First, an overview is given of the knowledge we have with respect to particle types, cross-linguistic dif„ferences, and their development over time. In the second part of the paper some of the gaps in our knowledge are identified, paying attention to subjects such as description, history, variation, translation and acquisition of particles. „Finally, it offers some suggestions as to the directions subsequent research might take.
Nederlandse partikels in het Portugees
Authors: Pos Arie
Published: April 2014

Dutch discourse, modal and focus particles are frequently considered to be a translator’s nightmare. This article takes translation into Portuguese as a case in point. Although at first sight translation seems to be problematic because of the lack of ready equivalents, a contrastive survey of different ways of expressing modal aspects in Portuguese and a more context-oriented functional approach to translation reveal that modal functions of Dutch particles can be expressed quite adequately in the target language. Can further contrastive research of Germanic and Romance languages help to clarify how particles really work?
Comparatieve neerlandistiek: de bestudering van de literatuur uit Nederland en Vlaanderen in het Duitse taalgebied sinds 1990
Authors: Konst Jan
Published: April 2014

This article discusses research on Dutch literature at universities in German-speaking countries since 1990. It appears that literary scholars in Dutch departments show a particular interest in a comparative approach. Dutch literature is studied in its international context and questions about, for example, the German reception of Dutch texts, German translations of Dutch literature and imagological topics are clearly dominant.
Transnationaal, maar toch neerlandistiek?
Authors: de Geest Dirk , Verstraeten Pieter
Published: April 2014

This article pleads for a ‘transnational approach’ to modern Dutch literature, with proper consideration of the national and even local perspective. In fact, the tension between local, national and international tendencies is one of the factors constituting the literary system. In this respect, the study of Dutch literature has been based on the romantic idea of a ‘nation state’ and a monolingual culture, thereby neglecting the essential role of transnational factors in establishing an autonomous literary system. The authors elaborate on this argument and present two examples (i.e. the success of international regional literature and the ambivalent reception of international modernism in Flanders) to illustrate this theoretical and methodological stance.
Transnationaliteit: Europese talen, literaturen en culturen in het perspectief van een postnationale horizon
Authors: Ehlich Konrad
Published: April 2014

Modern philologies are intrinsically bound to the ‘Nation Project’, a concept of substantial influence on language, literature, and culture from the eighteenth to twentieth centuries in Europe. As a consequence, philologies are basically national philologies. The situation of the twentyfirst century is of a post-national situation and is, thus, a challenge to the nation-bound concepts of language, literature, and culture. A major task for philologies is the development of new concepts that maintain the positive effects of the nation-bound concepts, and, at the same time, transform them into a post-national context. The term ‘transnational’ is meant to cover these transformation processes. Philologies can offer important contributions to a multilingual linguistic qualification on a par with the demands of knowledge based societies of the twentyfirst century.
Intercultureel – Transnationaal -- Europees: De opleiding Nederlands in een kleine cultuur- en taalgemeenschap vanuit translatologisch perspectief
Authors: Štefková Marketa , Brezániová Lucia
Published: April 2014

This article discusses the position of Dutch as a Foreign Language within the curriculum of Translating/Interpreting and Germanic Studies at the Faculty of Philosophy of the Comenius University in Bratislava and within the context of national and European language politics. First, it analyzes the development of language and culture of language in Slovakia and the manner in which that development influenced communication in the area of former Czechoslovakia. The role of Czech and Slovak in communication between Czechs and Slovaks is presented as 'lingua receptiva'. Subsequently, an intercultural and a transnational model for foreign language teaching from the perspective of translatology are compared, and their application in foreign language teaching is illustrated with reference to the example of Dutch as part of the newly developed BA ‘Germanic Studies’ at Comenius.
Een verkennend onderzoek naar taalverruwing
Authors: Renkema Jan
Published: April 2014

This paper consists of two parts. In the first part, an attempt will be made to define ‘rude language’ in a such way that it discerns itself from other types of negative language use. This definition uses concepts such as register, informalisation, appreciation, intensification and dysfemy. Possible problems with this definition are discussed with existing examples of ‘rude language’.

The second part of this paper explores to what extent the proposed definition can be used in empirical research. In a first survey after the effects of rude language, respondents have been asked their opinions about neutral or rude versions of (fictitious) newspaper items about political proposals. Results show that judgment is not related to personal traits such as age, gender, or political colour. Rude language does not affect the attitude towards the political proposal, but the proposing politician is perceived as less competent and attractive. Furthermore, it is judged as being less appropriate but more attractive than neutral language. This first experiment provides impetus for future research based on the proposed definition of rude language.
Lezen in de breedte - Kroniek van de literatuurwetenschap
Authors: Vervaeck Bart
Published: April 2014

Hoe gaat het met de literatuurwetenschap in Nederland en Vlaanderen? Goed, hoewel de literatuurwetenschap niet bestaat. Er zijn veel uiteenlopende varianten en die floreren zelfs in een klein taalgebied als dat van ons. Dat zou de al te korte samenvatting kunnen zijn van Tijding en tendens: Literatuurwetenschap in de Nederlanden. Het boek bevat negen teksten die in de inleiding met elkaar verbonden worden door hun ontstaanscontext (een congres in Leuven), hun centrale vraagstelling (hoe zit het met de eigenheid van de Nederlandstalige literatuurwetenschap én met haar verhouding tot de buitenlandse tradities?) en hun positie op het continuüm tussen literatuurwetenschap (theorie) en literatuurkritiek (praktijk).
‘Zitten is een werkwoord’: de erfenis van Berlage en Rietveld voor het ‘Nieuwe Bouwen’
Authors: Boers Marion
Published: April 2014

De Prins Hendriklaan in Utrecht is een typisch vooroorlogse Nederlandse straat met aan weerszijden ietwat sombere, keurige rijtjeshuizen. De meeste woningen hebben erkers om zo veel mogelijk zon in de woonkamers toe te laten. Op de eerste verdieping hebben sommige huizen een kneuterig balkon, meer een soort borstwering, en de dakrand boven de tweede verdieping steekt zo ver uit dat er nauwelijks licht binnenkomt in de ‘bodekamertjes’ onder het schuine dak. Van achter de vitrages zal men met de nodige argwaan naar buiten hebben geloerd, toen tussen 1923 en 1924 op de open kavel ernaast een vreemdsoortig bouwwerk verrees als woonhuis voor de eigenzinnige mevrouw Schröder-Schräder (1889- 1985).
Drie versies van Celan: Bernlef, Kuijper en Theunynck
Authors: de Strycker Carl
Published: April 2014

This article offers an interpretation of three poems that in their title refer to Paul Celan. This evokes a theoretical reflection on the question who is responsible for the intertextuality: the author, the text or the reader. With Eco’s notion of the intentio operis it is argued that the text itself contains signals that legitimize an intertextual reading. Then, with Riffaterre, the question is answered how to discover less explicite references and architexts. In the analysis of the poems of J. Bernlef, Jan Kuijper and Peter Theunynck I will indicate which verses of Celan they are referring to and how these verses function in the new text. In addition to this it is investigated how these poems fit into the poetics of their authors. Finally the different images of Celan that these poems create are discussed. In the conclusion I will return to the theoretical starting point of the article to determine the role of the reader in the intertextual reading.
‘Don’t be a fool, put a condom on your tool’ - Effecten van retorische figuren in hiv/aids-voorlichtingsmateriaal in Zuid-Afrika
Authors: Jansen Carel
Published: April 2014

The South African health organisation loveLife tries to provoke youths to talk about HIV/AIDS by presenting them with billboards and radio advertisements with messages that include complicated rhetorical figures that will supposedly puzzle them. In order to test the assumption that puzzlement about health messages is related to willingness to talk about these messages, two studies were carried out in Limpopo Province, South Africa. In the first study five loveLife billboards, together with a questionnaire, were presented to 149 freshmen. In the second study structured interviews were conducted with thirty secondary schools learners about six HIV/AIDS posters and six HIV/AIDS radio advertisements from loveLife and other South African health organisations. Neither in the first, nor in the second study was support found for the expectation that presenting youths with a puzzling health message will contribute to engaging them in discussions about the theme addressed in the message. By contrast, a positive correlation was found between the participants’ perceived comprehension of a message and their self-reported inclination to dialogue. No clear relations were found between the use of rhetorical figures (tropes or schemes) and the effects of the billboards and the radio messages. Participants indicated that they were willing to discuss the themes addressed in either a poster or radio advertisement because they appreciated the message and felt that its content was relevant to them, rather than because the message was puzzling or difficult to understand. The participants’ overall actual comprehension of the messages, however, proved to be strikingly low.
Impacts of Technology Uncertainty on Energy Use, Emission and Abatement Cost in USA: Simulation results from Environment Canada’s Integrated Assessment Model
Authors: Zhu Yunfa , Ghosh Madanmohan
Published: April 2014

To what extent could various technological advancements in the coming decades potentially help greenhouse gas mitigation in the U.S.? What could the potential contribution of end-use technology and other key clean electric energy technologies such as CCS, Nuclear power, wind & solar, and biomass be? This paper presents simulation results from an Integrated Assessment Model that suggest that, in the absence of policy measures, even under the most optimistic state of technology development and deployment scenarios, the U.S. energy system would still be dominated by fossil fuels and GHG emissions would increase significantly between 2010 and 2050. A pessimistic scenario in end-use technology would result in increased electric and non-electric energy use and GHG emissions compared to the advanced technology scenario, while a pessimistic scenario in any one of the four clean technologies examined would result in reduced electric and non-electric energy use and a small increase in GHG emissions. However, if all technologies are in pessimistic status, GHG emissions would increase significantly as more fossil fuels would be used in the energy system. Technology alone cannot achieve the abatement levels required. A market-based policy targeting the reduction of U.S. GHG emissions to 50% below 2005 levels by 2050 would result in dramatic decrease in coal-fired generation. With abatement policies in place, favorable technology scenarios reduce abatement costs and facilitate the energy system transition from fossil fuels to clean energy.
Greenhouse Gas Mitigation Options in the U.S. Electric Sector: A ReEDS Analysis
Authors: Sullivan Patrick , Uriarte Caroline , Short Walter
Published: April 2014

We apply a U.S. electric-sector capacity-expansion and dispatch model to assess possible implications—changes in generation mix, system cost, CO2 emissions, distribution of renewable energy deployment—of a set of potential greenhouse gas mitigation policy options over a range of technology projections. The model used, ReEDS, provides unique spatial and temporal detail to ensure electric-sys-tem constraints of reliable load provision are maintained throughout the system’s transformation.
Real-Time Lane Detection on Suburban Streets Using Visual Cue Integration
Authors: Fernando Shehan , Udawatta Lanka , Horan Ben , Pathirana Pubudu
Published: April 2014

The detection of lane boundaries on suburban streets using images obtained from video constitutes a challenging task. This is mainly due to the difficulties associated with estimating the complex geometric structure of lane boundaries, the quality of lane markings as a result of wear, occlusions by traffic, and shadows caused by road-side trees and structures. Most of the existing techniques for lane boundary detection employ a single visual cue and will only work under certain conditions and where there are clear lane markings. Also, better results are achieved when there are no other on-road objects present. This paper extends our previous work and discusses a novel lane boundary detection algorithm specifically addressing the abovementioned issues through the integration of two visual cues. The first visual cue is based on stripe-like features found on lane lines extracted using a two-dimensional symmetric Gabor filter. The second visual cue is based on a texture characteristic determined using the entropy measure of the predefined neighbourhood around a lane boundary line. The visual cues are then integrated using a rule-based classifier which incorporates a modified sequential covering algorithm to improve robustness. To separate lane boundary lines from other similar features, a road mask is generated using road chromaticity values estimated from CIE L*a*b* colour transformation. Extraneous points around lane boundary lines are then removed by an outlier removal procedure based on studentized residuals. The lane boundary lines are then modelled with Bezier spline curves. To validate the algorithm, extensive experimental evaluation was carried out on suburban streets and the results are presented.
A Practical Method for Implementing an Attitude and Heading Reference System
Authors: Munguía Rodrigo , Grau Antoni
Published: April 2014

This paper describes a practical and reliable algorithm for implementing an Attitude and Heading Reference System (AHRS). This kind of system is essential for real time vehicle navigation, guidance and control applications. When low cost sensors are used, efficient and robust algorithms are required for performance to be acceptable. The proposed method is based on an Extended Kalman Filter (EKF) in a direct configuration. In this case, the filter is explicitly derived from both the kinematic and error models. The selection of this kind of EKF configuration can help in ensuring a tight integration of the method for its use in filter-based localization and mapping systems in autonomous vehicles. Experiments with real data show that the proposed method is able to maintain an accurate and drift-free attitude and heading estimation. An additional result is to show that there is no ostensible reason for preferring that the filter have an indirect configuration over a direct configuration for implementing an AHRS system.