bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of accelerated aging upon the lipid composition of seeds from two soft wheat varieties from Morocco
Authors: Ouzouline M. , Tahani N. , Demandre C. , El Amrani E. , Benhassaine-Kesri G. , Serghini Caid H.
Published: May 2009

The lipid composition of the seeds from two soft wheat varieties (Triticum aestivum, cv. Marchouche and Mahdia) were analyzed before and after accelerated aging. Eight days of accelerated aging resulted in a total inhibition of seed germinability as well as a decrease in their total and especially unsaturated fatty acid contents. Oleic and linoleic acid contents decreased particularly in the phosphatidylcholine of the seeds from both varieties. The proportion of polar lipids also decreased after aging as compared to neutral lipids: a 5.8% and 7.2% decrease in polar lipids was e observed in Mahdia and Marchouche cultivars, respectively. In the neutral lipids of the seeds from the Marchouche variety, the percentage of free fatty acids increased whereas the triacylglycerols decreased. After aging, the fatty acid compositions of all lipid classes were modified in the same manner as total fatty acid compositions. Among polar lipids, phospholipid proportions were particularly small, especially the phosphatidylcholine percentages with an 18.1% and 19.1% decrease in Mahdia and Marchouche varieties, respectively. In contrast, MGDG percentages increased, especially in the seeds from the Marchouche variety. A 15.5% increase was noticed when compared with seeds which were not aged. At the same time, the DGDG percentage showed a 16.6% decrease after accelerated aging of the seeds from the Marchouche variety. From these results we concluded that the lipid content decrease observed in seeds after accelerated aging could be linked to a loss in the germination and vigor of wheat seeds.
Chemical composition and sensory analysis of peanut pastes elaborated with high-oleic and regular peanuts from Argentina
Authors: Riveros Cecilia G. , Mestrallet M. G. , Nepote V. , Grosso N. R.
Published: May 2009

The objective of this work was to determine the chemical composition, sensory attributes and consumer acceptance of peanut pastes prepared with the high-oleic cultivar, Granoleico (GO-P), in comparison with the regular cultivar, Tegua (T-P), of peanuts grown in Argentina. GO-P had higher oil contents (50.91%) than T-P (48.95%). GO-P and T-P did not show differences in ash and carbohydrate contents. T-P exhibit higher protein content (27.49%) than GO-P (26.68%). GO-P had significantly higher oleic and lower linoleic contents (78.50% and 4.60%, respectively) than T-P (45.80% and 33.30%, respectively). In addition, GO-P showed higher eicosenoic acid and lower palmitic acid percentages than TP. The consumer acceptance analysis did not show significant differences between samples of GO-P and T-P. In the descriptive analysis, GO-P showed a higher intensity rating in the oiliness texture attribute than in T-P. The other sensory attributes did not show significant variations between the peanut paste samples. GO-P and T-P have a significant difference in fatty acid composition. However, there were no differences in consumer acceptance and descriptive analysis between samples of peanut pastes except for the oiliness attribute.
Determination of fatty acid, tocopherol and phytosterol contents of the oils of various poppy (Papaver somniferum L.) seeds.
Authors: Erinç Hakan , Tekin Aziz , Musa Özcan Mehmet
Published: May 2009

The fatty acid, tocopherol and sterol contents of the oils of several poppy seeds were investigated. The main fatty acids in poppy seed oils were linoleic (687.6-739.2 g kg-1), oleic (141.3-192.8 g kg-1) and palmitic (76.8-92.8 g kg-1). The oils contained an appreciable amount of -tocopherol (195.37-280.85 mg kg-1), with a mean value of 261.31 mg kg-1 and α-tocopherol (21.99-45.83 mg kg-1), with a mean value of 33.03 mg kg-1. The concentrations of total sterol ranged from 1099.84 mg kg-1 (K.pembe) to 4816.10 mg kg-1 (2. sınıf beyaz), with a mean value of 2916.20 mg kg-1. The major sterols were -sitosterol, ranging from 663.91 to 3244.39 mg kg-1; campesterol, ranging from 228.59 to 736.50 mg kg-1; and Δ5-avenasterol, ranging from 103.90 to 425.02 mg kg-1. The studied varieties of poppy seeds from Turkey were found to be a potential source of valuable oil.
El trabajo en beneficio de la comunidad como alternativa a la prisión. Entre la aceptación y el rechazo
Authors: Albalate Joaquín Juan
Published: May 2009

El debate sobre las medidas alternativas a la prisión y, en particular, sobre el trabajo en beneficio de la comunidad, ha adquirido un renovado interés durante los últimos años, a raíz del progresivo aumento de la población reclusa española. Partiendo de las diversas teorías que existen sobre la pena, se pretende mostrar que, tras más de diez años de haberse aprobado el Código penal vigente, esa medida, aunque ha experimentado recientemente una notable expansión, sigue sin alcanzar su máximo desarrollo, a pesar de los efectos positivos ya demostrados en otros países de nuestro entorno, en cuanto a su mayor eficacia en la reinserción social de las personas encausadas y, por consiguiente, en la disminución de la densidad carcelaria.
Anillos de crecimiento en el árbol de la ciencia. La evolución institucional del Consejo Superior de Investigaciones Científicas
Authors: Fernández-Esquinas Manuel , Sebastián Jesús , López-Facal Javier , Tortosa-Martorell Enrique
Published: May 2009

¿Cuáles son los factores que influyen en los modelos organizativos de los grandes centros públicos de investigación de ámbito nacional? ¿Cómo afectan los cambios a la naturaleza de la actividad científica que realizan? Este artículo utiliza el caso del CSIC para estudiar un proceso de cambio organizativo teniendo en cuenta la tensión entre la dependencia del Estado de estos centros y el alto nivel de autonomía de sus comunidades científicas. El principal propósito es explicar cómo la transformación de la estructura de autoridad, junto a la dependencia de agencias de financiación y evaluación, da lugar a la emergencia de las prácticas de investigación consideradas más legítimas y a una reorientación de la actividad científica del conjunto del organismo. Para ello se realiza una narrativa histórica de la situación del CSIC en el periodo comprendido entre la Transición a la Democracia y los inicios del siglo XXI. La narrativa está informada teóricamente por conceptos del enfoque institucional en la sociología de las organizaciones. Los resultados muestran cómo el CSIC se ha convertido en una organización orientada a la ciencia básica. Las conclusiones ofrecen implicaciones para los estudios sociales sobre la ciencia y para las políticas científicas en este campo.
Hable con los pacientes, no para ellos. Análisis de las fuentes de confianza del acto médico
Authors: Loriente-Arín Nuria , Serrano-del-Rosal Rafael
Published: May 2009

Diferentes estudios se han centrado en definir cuáles son los papeles que deben adoptar médico y paciente durante su relación en la consulta en aras de conseguir altos niveles de satisfacción del usuario y confianza en la asistencia recibida. Elementos ambos de suma importancia para incrementar la probabilidad de seguir los consejos y tratamientos del médico, aspectos indicativos del éxito de dicha consulta. Dada la inexistencia de un consenso claro entre los investigadores, este trabajo se ha centrado en estudiar empíricamente, a partir de los datos de la Encuesta a usuarios de los Servicios de Atención Primaria prestados por el Servicio Andaluz de Salud en 2006, cómo varía la confianza en la asistencia médica en función de las evaluaciones que realizan los usuarios sobre diferentes aspectos del acto médico. Los resultados apuntan que las condiciones de una relación médico-paciente exitosa se basan principalmente en mantener una verdadera comunicación y no un mero intercambio de información.
El fenómeno de la sobreeducación en Europa
Authors: Budría Santiago , Moro-Egido Ana I.
Published: May 2009

En la literatura relacionada con la sobre-educación, es tradicional asumir que el impacto de dicha sobreeducación en los salarios es común a toda la distribución de salarios. En este artículo, con datos de un grupo de países europeos y utilizando la regresión cuantílica se demuestra que, de hecho, el impacto de la sobreeducación es diferente en los distintos segmentos de la distribución de salarios. Las diferencias de género y por país son también significativas. Así por ejemplo en Alemania, la penalización salarial de los sobreeducados es mayor entre las mujeres que entre los hombres, pero mientras para los hombres la penalización es mayor en los deciles superiores, para las mujeres la penalización es mayor en los deciles inferiores. En España, las mujeres son más severamente penalizadas por estar sobre-educadas que los hombres, siendo constante dicha penalización salarial a lo largo de la distribución de salarios.
Comentario a "Por un giro analítico en Sociología"
Authors: Caínzos Miguel
Published: May 2009

No disponible.
Comentarios sobre "Por un giro analítico en la sociología" de Aguiar, de Francisco y Noguera
Authors: González de la Fe Teresa
Published: May 2009

No disponible.
El "momento" analítico. Poniendo bridas al pensamiento desbocado
Authors: Lamo de Espinosa Emilio
Published: May 2009

No disponible.
Sociología analítica
Authors: Solé Carlota
Published: May 2009

No disponible.
Chronic Antigen Stimulation Alone Is Sufficient to Drive CD8+ T Cell Exhaustion
Authors: Bucks Christine M. , Norton Jillian A. , Boesteanu Alina C. , Mueller Yvonne M. , Katsikis Peter D.
Published: May 2009

The failure of CD8+ T cells to respond to chronic infection has been termed “exhaustion” and describes the condition in which CD8+ T cells exhibit reduced differentiation, proliferation, and effector function. CD8+ T cell exhaustion has been extensively studied in the murine model of chronic infection, lymphocytic choriomeningitis virus (LCMV). Although LCMV-based studies have yielded many interesting findings, they have not allowed for discrimination between the roles of cytokine- and Ag-driven exhaustion. We have created a system of chronic Ag stimulation using murine influenza A virus that leads to exhaustion and functional disability of virus-specific CD8+ T cells, in the absence of high viral titers, sustained proinflammatory cytokine production and lymphocyte infection. Our findings show that Ag alone is sufficient to drive CD8+ T cell impairment, that Ag-driven loss of virus-specific CD8+ T cells is TRAIL mediated, and that removal of Ag reverses exhaustion. Although programmed death 1 was up-regulated on chronic Ag-stimulated CD8+ T cells, it played no role in the exhaustion. These findings provide a novel insight into the mechanisms that control functional exhaustion of CD8+ T cells in chronic infection.
Dexamethasone and FK506 Inhibit Expression of Distinct Subsets of Chemokines in Human Mast Cells
Authors: Kato Atsushi , Chustz Regina T. , Ogasawara Takahisa , Kulka Marianna , Saito Hirohisa , Schleimer Robert P. , Matsumoto Kenji
Published: May 2009

Mast cells produce a large amount of several chemokines after cross-linking of FcεRI and participate in the pathogenesis of allergic diseases. The objective of this study was to comprehensively investigate FcεRI-mediated chemokine induction in human mast cells and the effect of a corticosteroid (dexamethasone) and a calcineurin inhibitor (FK506). Human peripheral blood-derived mast cells were stimulated with anti-IgE Ab in the presence of dexamethasone or FK506. Gene expression profiles were evaluated using GeneChip and confirmed by real-time PCR, and chemokine concentrations were measured by cytometric bead arrays and ELISA. Expression of eight chemokines was significantly induced in mast cells by anti-IgE stimulation. Induction of CCL2, CCL7, CXCL3, and CXCL8 by anti-IgE was significantly inhibited by dexamethasone but was enhanced by FK506. In contrast, induction of CCL1, CCL3, CCL4, and CCL18 was significantly inhibited by FK506 but, with the exception of CCL1, was enhanced by dexamethasone. Combination of dexamethasone and FK506 suppressed production of all chemokines by anti-IgE stimulation. Studies using protease inhibitors indicate that mast cell proteases may degrade several of the chemokines. These results suggest that corticosteroids and calcineurin inhibitors inhibit expression of distinct subsets of chemokines, and a combination of these drugs almost completely suppresses the induction of all chemokine genes in human mast cells in response to FcεRI-dependent stimulation. This implies that a combination of a corticosteroid and a calcineurin inhibitor may be more effective than each single agent for the treatment of allergic diseases in which mast cell-derived chemokines play a major role.
The CysLT1 Ligand Leukotriene D4 Supports α4β1- and α5β1-Mediated Adhesion and Proliferation of CD34+ Hematopoietic Progenitor Cells
Authors: Boehmler Andreas M. , Drost Adriana , Jaggy Lena , Seitz Gabriele , Wiesner Tina , Denzlinger Claudio , Kanz Lothar , Möhle Robert
Published: May 2009

Cytokines and chemokines control hematopoietic stem and progenitor cell (HPC) proliferation and trafficking. However, the role of nonpeptide mediators in the bone marrow microenvironment has remained elusive. Particularly CysLT1, a G protein-coupled receptor recognizing inflammatory mediators of the cysteinyl leukotriene family, is highly expressed in HPCs. We therefore analyzed the effects of its ligands on human CD34+ HPCs. The most potent CysLT1 ligand, LTD4, rapidly and significantly up-regulated α4β1 and α5β1 integrin-dependent adhesion of both primitive and committed HPC. LTD4-triggered adhesion was inhibited by specific CysLT1 antagonists. The effects of other CysLT1 ligands were weak (LTC4) or absent (LTE4). In serum-free liquid cultures supplemented with various hematopoietic cytokines including IL-3, only LTD4 significantly augmented the expansion of HPCs in a dose-dependent manner comparable to that of peptide growth factors. LTC4 and LTE4 were less effective. In CD34+ cell lines and primary HPCs, LTD4 induced phosphorylation of p44/42 ERK/MAPK and focal adhesion kinase-related tyrosine kinase Pyk2, which is linked to integrin activation. Bone marrow stromal cells produced biologically significant amounts of cysteinyl leukotrienes only when hematopoietic cells were absent, suggesting a regulatory feedback mechanism in the hematopoietic microenvironment. In contrast to antagonists of the homing-related G protein-coupled receptor CXCR4, administration of a CysLT1 antagonist failed to induce human CD34+ HPC mobilization in vivo. Our results suggest that cysteinyl leukotriene may contribute to HPC retention and proliferation only when cysteinyl leukotriene levels are increased either systemically during inflammation or locally during marrow aplasia.
Antigen Load Governs the Differential Priming of CD8 T Cells in Response to the Bacille Calmette Guérin Vaccine or Mycobacterium tuberculosis Infection
Authors: Ryan Anthony A. , Nambiar Jonathan K. , Wozniak Teresa M. , Roediger Ben , Shklovskaya Elena , Britton Warwick J. , Fazekas de St. Groth Barbara , Triccas James A.
Published: May 2009

One reason proposed for the failure of Mycobacterium bovis bacille Calmette Guérin (BCG) vaccination to adequately control the spread of tuberculosis is a limited ability of the vaccine to induce effective CD8 T cell responses. However, the relative capacity of the BCG vaccine and virulent Mycobacterium tuberculosis to induce activation of CD8 T cells, and the factors that govern the initial priming of these cells after mycobacterial infection, are poorly characterized. Using a TCR transgenic CD8 T cell transfer model, we demonstrate significant activation of Ag-specific CD8 T cells by BCG, but responses were delayed and of reduced magnitude compared with those following infection with M. tuberculosis. The degree of CD8 T cell activation was critically dependent on the level of antigenic stimulation, as modifying the infectious dose to achieve comparable numbers of BCG or M. tuberculosis in draining lymph nodes led to the same pattern of CD8 T cell responses to both strains. Factors specific to M. tuberculosis infection did not influence the priming of CD8 T cells, as codelivery of M. tuberculosis with BCG did not alter the magnitude of BCG-induced T cell activation. Following transfer to RAG-1−/− recipients, BCG and M. tuberculosis-induced CD8 T cells conferred equivalent levels of protection against M. tuberculosis infection. These findings demonstrate that BCG is able to prime functional CD8 T cells, and suggest that effective delivery of Ag to sites of T cell activation by vaccines may be a key requirement for optimal CD8 T cell responses to control mycobacterial infection.
IL-15 Renders Conventional Lymphocytes Resistant to Suppressive Functions of Regulatory T Cells through Activation of the Phosphatidylinositol 3-Kinase Pathway
Authors: Ahmed Mélika Ben , Belhadj Hmida Nadia , Moes Nicolette , Buyse Sophie , Abdeladhim Maha , Louzir Hechmi , Cerf-Bensussan Nadine
Published: May 2009

IL-15 drives chronic inflammation in several human diseases. We have recently shown that IL-15 inhibits the immunosuppressive effects of TGF-β through blockage of the Smad3-signaling pathway. Data pointing to reciprocal interactions between TGF-β and CD4+ regulatory T cells led us to investigate the impact of IL-15 on the de novo generation and function of regulatory T cells in humans. Our data indicate that IL-15 does not counteract, but rather promotes the effect of TGF-β on the de novo generation of regulatory T cells (Treg). Thus, in the presence of TGF-β, IL-15 enhanced the acquisition of regulatory functions by CD4+CD25− T cells stimulated by anti-CD3 and anti-CD28 Abs. In contrast, IL-15 impaired the functions of Tregs by acting on effector CD4 and CD8 T cells. Accordingly, in the presence of IL-15, proliferation and IFN-γ production by peripheral CD4 and CD8 T cells could not be efficiently inhibited by Tregs. IL-15-induced resistance of effector T cells to Tregs resulted from activation of the PI3K signaling pathway but did not involve the rescue of effector T cells from apoptosis. Altogether, these data point to the ambiguous role of IL-15 in the control of Treg functions. This dual role may be instrumental to mount rapid but transient proinflammatory immune responses against pathogens but may become deleterious in situations associated with protracted IL-15 over-expression.
Chemokine Receptor CCR7 Contributes to a Rapid and Efficient Clearance of Lytic Murine γ-Herpes Virus 68 from the Lung, Whereas Bronchus-Associated Lymphoid Tissue Harbors Virus during Latency
Authors: Kocks Jessica R. , Adler Heiko , Danzer Heike , Hoffmann Katharina , Jonigk Danny , Lehmann Ulrich , Förster Reinhold
Published: May 2009

Murine γ-herpes virus 68 is a natural rodent pathogen closely related to the human γ-herpes viruses Kaposi’s sarcoma-associated herpes virus and EBV. By intranasally infecting wild-type and CCR7-deficient mice, we investigated whether CCR7 is necessary for viral clearance from the lung and the establishment of latency. We found during the lytic phase of infection that inflammation in lungs of CCR7−/− mice was more severe and viral load significantly higher compared with wild-type littermates. In addition, activation of T cells was delayed and clearance of the inflammation was retarded in mutant lungs, demonstrating that CCR7 is necessary for a rapid and efficient immune response. However, for the establishment of splenomegaly and latency, the presence of CCR7 was dispensable. Finally, by microdissecting BALT, we could demonstrate that these ectopic lymphoid structures are a place in the lung where virus resides during latency.
CD2 Distinguishes Two Subsets of Human Plasmacytoid Dendritic Cells with Distinct Phenotype and Functions
Authors: Matsui Toshimichi , Connolly John E. , Michnevitz Mark , Chaussabel Damien , Yu Chun-I , Glaser Casey , Tindle Sasha , Pypaert Marc , Freitas Heidi , Piqueras Bernard , Banchereau Jacques , Palucka A. Karolina
Published: May 2009

Plasmacytoid dendritic cells (pDCs) are key regulators of antiviral immunity. They rapidly secrete IFN-α and cross-present viral Ags, thereby launching adaptive immunity. In this study, we show that activated human pDCs inhibit replication of cancer cells and kill them in a contact-dependent fashion. Expression of CD2 distinguishes two pDC subsets with distinct phenotype and function. Both subsets secrete IFN-α and express granzyme B and TRAIL. CD2high pDCs uniquely express lysozyme and can be found in tonsils and in tumors. Both subsets launch recall T cell responses. However, CD2high pDCs secrete higher levels of IL12p40, express higher levels of costimulatory molecule CD80, and are more efficient in triggering proliferation of naive allogeneic T cells. Thus, human blood pDCs are composed of subsets with specific phenotype and functions.
Identification of an IFN-γ-Producing Neutrophil Early in the Response to Listeria monocytogenes
Authors: Yin Jiyi , Ferguson Thomas A.
Published: May 2009

IFN-γ plays a critical role during the immune response to infection with Listeria monocytogenes. Early in the innate response NK cells are thought to be a primary source of IFN-γ; however, protection can be mediated by the presence of significant numbers of primed IFN-γ-secreting CD8+ T cells. In this report, we examined the early response to Listeria and found that 18 h after infection spleens contain CD11b+, Gr-1high, or Ly6G+ cells that produce significant IFN-γ. Morphological analysis of sorted Gr-1highIFN-γ+ and Gr-1lowIFN-γ+ or Ly6G+IFN-γ+ cells confirmed that these cells were neutrophils. The importance of IFN-γ production by these cells was further tested using adoptive transfer studies. Transfer of purified neutrophils from Ifng+/+ mice led to increased bacterial clearance in Ifng−/− mice. Transfer of Ifng−/− neutrophils provided no such protection. We conclude that neutrophils are an early source of IFN-γ during Listeria infection and are important in providing immune protection.
Pollen-Derived E1-Phytoprostanes Signal via PPAR-γ and NF-κB-Dependent Mechanisms
Authors: Gilles Stefanie , Mariani Valentina , Bryce Martina , Mueller Martin J. , Ring Johannes , Jakob Thilo , Pastore Saveria , Behrendt Heidrun , Traidl-Hoffmann Claudia
Published: May 2009

In a humid milieu such as mucosal surfaces, pollen grains do not only release allergens but also proinflammatory and immunomodulatory lipids, termed pollen-associated lipid mediators. Among these, the E1-phytoprostanes (PPE1) were identified to modulate dendritic cell (DC) function: PPE1 inhibit the DC’s capacity to produce IL-12 and enhance DC mediated TH2 polarization of naive T cells. The mechanism(s) by which PPE1 act on DC remained elusive. We thus analyzed candidate signaling elements and their role in PPE1-mediated regulation of DC function. Aqueous birch pollen extracts induced a marked cAMP response in DC that could be blocked partially by EP2 and EP4 antagonists. In contrast, PPE1 hardly induced cAMP and the inhibitory effect on IL-12 production was mostly independent of EP2 and EP4. Instead, PPE1 inhibited the LPS-induced production of IL-12 p70 by a mechanism involving the nuclear receptor PPAR-γ. Finally, PPE1 efficiently blocked NF-κB signaling in DCs by inhibiting IκB-α degradation, translocation of p65 to the nucleus, and binding to its target DNA elements. We conclude that pollen-derived PPE1 modulate DC function via PPAR-γ dependent pathways that lead to inhibition of NFκB activation and result in reduced DC IL-12 production and consecutive TH2 polarization.
TLR2 Deficiency Leads to Increased Th17 Infiltrates in Experimental Brain Abscesses
Authors: Nichols Jessica R. , Aldrich Amy L. , Mariani Monica M. , Vidlak Debbie , Esen Nilufer , Kielian Tammy
Published: May 2009

TLR2 plays a pivotal role in recognizing Staphylococcus aureus, a common etiologic agent of CNS parenchymal infections, such as brain abscess. We previously reported that brain abscesses of TLR2 knockout (KO) mice exhibited elevated IL-17 levels, suggesting the presence of an alternative pathway available to respond to S. aureus infection that may involve Th17 cells. Both CD4+ and CD8+ T cell infiltrates were elevated in brain abscesses of TLR2 KO mice at days 3, 7, and 14 postinfection compared with wild-type animals. Intracellular cytokine staining revealed a significant increase in the frequency of IL-17-producing Th17 cells in TLR2 KO mice with relatively few IFN-γ-positive cells. γδ T cells were also a source of IL-17 in brain abscesses. Microglia, astrocytes, and macrophages were shown to express both IL-17RA and IL-17RC. Despite receptor expression, IL-17 was relatively ineffective at eliciting glial activation, whereas the cytokine augmented the ability of TNF-α to induce CXCL2 and CCL2 expression by macrophages. Based on the ability of IL-17 to elicit the release of chemokines and other proinflammatory mediators, we propose that the exaggerated IL-17 response that occurs in TLR2 KO mice functions in a compensatory manner to control brain abscess pathogenesis, with cells other than glia as targets for IL-17 action. This is supported by our findings in which innate immune infiltrates were not significantly different between TLR2 KO and wild-type mice in conjunction with the lack of prolonged alterations in the synthesis of other proinflammatory molecules during the course of infection.
TLR Activation Induces TNF-α Production from Adult Neural Stem/Progenitor Cells
Authors: Covacu Ruxandra , Arvidsson Lisa , Andersson Åsa , Khademi Mohsen , Erlandsson-Harris Helena , Harris Robert A. , Svensson Mikael A. , Olsson Tomas , Brundin Lou
Published: May 2009

Adult neural stem cells (NSCs) are believed to facilitate CNS repair and tissue regeneration. However, it is not yet clear how these cells are influenced when the cellular environment is modified during neurotrauma or neuroinflammatory conditions. In this study, we determine how different proinflammatory cytokines modulate the expression of TLR2 and TLR4 in NSCs and how these cells respond to TLR2 and TLR4 agonists. Primary cultures of neural stem/progenitor cells isolated from the subventricular zone of brains from adult Dark Agouti rats were exposed to 1) supernatants from activated macrophages; 2) proinflammatory cytokines IFN-γ, TNF-α, or both; and 3) agonists for TLR2 and TLR4. Both TLR2 and TLR4 were expressed during basal conditions and their mRNA levels were further increased following cytokine exposure. TLR4 was up-regulated by IFN-γ and this effect was reversed by TNF-α. TLR2 expression was increased by supernatants from activated macrophages and by TNF-α, which synergized with IFN-γ. TLR agonists induced the expression of TNF-α mRNA. Importantly, TNF-α could be translated into protein and released into the supernatants where it was quantified by cytokine ELISA. In conclusion, we demonstrate that NSCs constitutively express TLR2 and TLR4 and that their expression is increased as a consequence of exposure to proinflammatory mediators. Additionally, activation of these receptors can induce production of proinflammatory cytokines. These findings suggest that NSCs may be primed to participate in cytokine production during neuroinflammatory or traumatic conditions.
The Chicken Leukocyte Receptor Complex Encodes a Family of Different Affinity FcY Receptors
Authors: Viertlboeck Birgit C. , Schweinsberg Sonja , Schmitt Ramona , Herberg Friedrich W. , Göbel Thomas W.
Published: May 2009

Chicken Ig-like receptors (CHIR) form a large family in the leukocyte receptor complex on microchromosome 31 with inhibitory, activating, and bifunctional receptors. Recently, we characterized CHIR-AB1 as a high-affinity, primordial FcY receptor. Given that the CHIR family represents a multigene family, it is plausible that more than a single receptor binds to IgY. Therefore, after comparing CHIR-AB1-like sequences in databases, we cloned CHIR-AB1 homologues from two individual chickens representing the lines M11 and R11 with primers binding to highly conserved regions. In both lines this approach yielded 18 different CHIR-AB amino acid versions, with one sequence out of each line that was identical with the previously characterized B19 CHIR-AB1 Ig domain and two additional R11-M11 identical sequence pairs. All M11-derived CHIR-AB homologues were then expressed as soluble human Ig fusion proteins. Following standardization of the fusion protein concentration with an ELISA, the IgY, IgM, and IgA binding activities were determined by ELISA. Six fusion proteins recognized IgY, whereas none bound to IgM and IgA. The affinities of selected fusion proteins were determined using surface plasmon resonance yielding an equilibrium binding constant between 25 nM for high binders and 260 nM for low binders. Sequence comparisons and subsequent mutational analysis of selected residues identified five amino acids that are potentially involved in IgY binding. These results imply that multiple FcY receptors of variable affinity are encoded by the CHIR locus and that different chicken lines may express both unique as well as highly conserved FcY receptors.
Dominant Human CD8 T Cell Clonotypes Persist Simultaneously as Memory and Effector Cells in Memory Phase
Authors: Touvrey Cédric , Derré Laurent , Devevre Estelle , Corthesy Patricia , Romero Pedro , Rufer Nathalie , Speiser Daniel E.
Published: May 2009

The adaptive immune system plays a critical role in protection at the time of secondary infection. It does so through the rapid and robust reactivation of memory T cells which are maintained long-term, in a phenotypically heterogeneous state, following their primary encounter with Ag. Although most HLA-A*0201/influenza matrix protein58–66-specific CD8 T cells from healthy donors display characteristics typical of memory T cells, through our extensive phenotypic analysis we have further shown that up to 20% of these cells express neither the IL-7 receptor CD127 nor the costimulatory molecule CD28. In contrast to the majority of CD28pos cells, granzyme B and perforin were frequently expressed by the CD28neg cells, suggesting that they are effector cells. Indeed, these cells were able to kill target cells, in an Ag-specific manner, directly ex vivo. Thus, our findings demonstrate the remarkable long-term persistence in healthy humans of not only influenza-specific memory cells, but also of effector T cells. We further observed that granzyme B expression in influenza-specific CD8 T cells paralleled levels in the total CD8 T cell population, suggestive of Ag-nonspecific bystander activation. Sequencing of TCR α- and β-chains showed that the TCR repertoire specific for this epitope was dominated by one, or a few, T cell clonotype per healthy donor. Moreover, our sequencing analysis revealed, for the first time in humans, that identical clonotypes can coexist as both memory and effector T cells, thereby supporting the principle of multipotent clonotypic differentiation.
The CD4+ T Cell-Mediated IFN-γ Response to Helicobacter Infection Is Essential for Clearance and Determines Gastric Cancer Risk
Authors: Sayi Ayca , Kohler Esther , Hitzler Iris , Arnold Isabelle , Schwendener Reto , Rehrauer Hubert , Müller Anne
Published: May 2009

Chronic infection with the bacterial pathogen Helicobacter pylori is a risk factor for the development of gastric cancer, yet remains asymptomatic in the majority of individuals. We report here that the C57BL/6 mouse model of experimental infection with the closely related Helicobacter felis recapitulates this wide range in host susceptibility. Although the majority of infected animals develop premalignant lesions such as gastric atrophy, compensatory epithelial hyperplasia, and intestinal metaplasia, a subset of mice is completely protected from preneoplasia. Protection is associated with a failure to mount an IFN-γ response to the infection and with a concomitant high Helicobacter burden. Using a vaccine model as well as primary infection and adoptive transfer models, we demonstrate that IFN-γ, secreted predominantly by CD4+CD25− effector TH cells, is essential for Helicobacter clearance, but at the same time mediates the formation of preneoplastic lesions. We further provide evidence that IFN-γ triggers a common transcriptional program in murine gastric epithelial cells in vitro and in vivo and induces their preferential transformation to the hyperplastic phenotype. In summary, our data suggest a dual role for IFN-γ in Helicobacter pathogenesis that could be the basis for the differential susceptibility to H. pylori-induced gastric pathology in the human population.
Coronin-1 Is Associated with Neutrophil Survival and Is Cleaved during Apoptosis: Potential Implication in Neutrophils from Cystic Fibrosis Patients
Authors: Moriceau Sandra , Kantari Chahrazade , Mocek Julie , Davezac Noélie , Gabillet Julie , Guerrera Ida Chiara , Brouillard Frank , Tondelier Danielle , Sermet-Gaudelus Isabelle , Danel Claire , Lenoir Gérard , Daniel Soizic , Edelman Aleksander , Witko-Sarsat Véronique
Published: May 2009

Because neutrophil apoptosis plays a key role in resolving inflammation, identification of proteins regulating neutrophil survival should provide new strategies to modulate inflammation. Using a proteomic approach, coronin-1 was identified as a cytosolic protein cleaved during neutrophil apoptosis. Coronin-1 is an actin-binding protein that can associate with phagosomes and NADPH oxidase, but its involvement in apoptosis was currently unknown. In coronin-1-transfected PLB985 cells, coronin-1 overexpression did not modify the kinetics of granulocyte differentiation as assessed by CD11b labeling. Concerning apoptosis, increased coronin-1 expression in dimethylformamide-differentiated PLB985 significantly decreased gliotoxin-induced mitochondrial depolarization as compared with controls. Likewise, coronin-1 significantly decreased TRAIL-induced apoptosis with less mitochondrial depolarization, caspase-3 and caspase-9 activities, but not caspase-8 or Bid truncation suggesting that coronin-1 interfered with mitochondria-related events. To validate the prosurvival role of coronin-1 in a pathophysiological condition involving neutrophil-dominated inflammation, neutrophils from cystic fibrosis (CF) patients were studied. Circulating neutrophils from CF patients had more coronin-1 expression assessed by immunoblotting or proteomic analysis of cytosolic proteins. This was associated with a lower apoptosis rate than those from controls evidenced by delayed phosphatidylserine externalization and mitochondria depolarization. In addition, inflammatory neutrophils from CF patients lungs showed an intense coronin-1 immunolabeling. We concluded that coronin-1 could constitute a potential target in resolving inflammation.
IL-7 Promotes CXCR3 Ligand-Dependent T Cell Antitumor Reactivity in Lung Cancer
Authors: Andersson Åsa , Yang Seok-Chul , Huang Min , Zhu Li , Kar Upendra K. , Batra Raj K. , Elashoff David , Strieter Robert M. , Dubinett Steven M. , Sharma Sherven
Published: May 2009

We are evaluating the immune enhancing activities of cytokines for their optimum utility in augmenting cellular immune responses against lung cancer. In this study, we evaluated the mechanism of antitumor responses following IL-7 administration to mice bearing established Lewis lung cancer. IL-7 decreased tumor burden with concomitant increases in the frequency of CD4 and CD8 T lymphocyte subsets, T cell activation markers CXCR3, CD69, and CD127low, effector memory T cells, and T cell cytolytic activity against parental tumor cells. Accompanying the antitumor responses were increases in IFN-γ, CXCL9, CXCL10, and IL-12. Individual neutralization of CD4, CD8 T lymphocytes, or the CXCR3 ligands CXCL9 and CXCL10 reversed the antitumor benefit of IL-7, indicating their importance for optimal responses in vivo. Furthermore, IL-7 decreased the tumor-induced apoptosis of T cells with subsequent decrease of the proapoptotic marker Bim. We assessed the impact of IL-7 treatment on regulatory T cells that negatively impact antitumor immune responses. IL-7 decreased regulatory T Foxp3 as well as cell suppressive activity with a reciprocal increase in SMAD7. These results indicate that IL-7 induces CXCR3 ligand-dependent T cell antitumor reactivity in lung cancer.
Vav1 Is Essential for Mechanotactic Crawling and Migration of Neutrophils out of the Inflamed Microvasculature
Authors: Phillipson Mia , Heit Bryan , Parsons Sean A. , Petri Björn , Mullaly Sarah C. , Colarusso Pina , Gower R. Michael , Neely Gregory , Simon Scott I. , Kubes Paul
Published: May 2009

Mac-1-dependent crawling is a new step in the leukocyte recruitment cascade that follows LFA-1-dependent adhesion and precedes emigration. Neutrophil adhesion via LFA-1 has been shown to induce cytoskeletal reorganization through Vav1-dependent signaling, and the current study investigates the role of Vav1 in the leukocyte recruitment process in vivo with particular attention to the events immediately downstream of LFA-1-dependent adhesion. Intravital and spinning-disk-confocal microscopy was used to investigate intravascular crawling in relation to endothelial junctions in vivo in wild-type and Vav1−/− mice. Adherent wild-type neutrophils almost immediately began crawling perpendicular to blood flow via Mac-1 until they reached an endothelial junction where they often changed direction. This pattern of perpendicular, mechanotactic crawling was recapitulated in vitro when shear was applied. In sharp contrast, the movement of Vav1−/− neutrophils was always in the direction of flow and appeared more passive as if the cells were dragged in the direction of flow in vivo and in vitro. More than 80% of Vav1−/− neutrophils moved independent of Mac-1 and could be detached with LFA-1 Abs. An inability to release the uropod was frequently noted for Vav1−/− neutrophils, leading to greatly elongated tails. The Vav1−/− neutrophils failed to stop or follow junctions and ultimately detached, leading to fewer emigrated neutrophils. The Vav1−/− phenotype resulted in fewer neutrophils recruited in a relevant model of infectious peritonitis. Clearly, Vav1 is critical for the complex interplay between LFA-1 and Mac-1 that underlies the programmed intravascular crawling of neutrophils.
CCR7-CCL19/CCL21-Regulated Dendritic Cells Are Responsible for Effectiveness of Sublingual Vaccination
Authors: Song Joo-Hye , Kim Jung-Im , Kwon Hyung-Joon , Shim Doo-Hee , Parajuli Nirmala , Cuburu Nicolas , Czerkinsky Cecil , Kweon Mi-Na
Published: May 2009

Our previous studies demonstrated the potential of the sublingual (s.l.) route for delivering vaccines capable of inducing mucosal as well as systemic immune responses. Those findings prompted us to attempt to identify possible inductive mechanism of s.l. vaccination for immune responses. Within 2 h after s.l. administration with cholera toxin (CT), significantly higher numbers of MHC class II+ cells accumulated in the s.l. mucosa. Of note, there were brisk expression levels of both CCL19 and CCL21 in cervical lymph nodes (CLN) 24 h after s.l. vaccination with CT. In reconstitution experiments using OVA-specific CD4+ or CD8+ T cells, s.l. vaccination elicited strong Ag-specific T cell proliferation mainly in CLN. Interestingly, Ag-specific T cell proliferation completely disappeared in CD11c-depleted and CCR7−/− mice but not in Langerin-depleted, macrophage-depleted, and CCR6−/− mice. Similar to CD4+ T cell responses, induction of Ag-specific IgG (systemic) and IgA (mucosal) Ab responses were significantly reduced in CD11c-depleted and CCR7−/− mice after s.l. vaccination with OVA plus CT. Although CD8α− dendritic cells ferried Ag from the s.l. mucosa, both migratory CD8α− and resident CD8α+ dendritic cells were essential to prime CD4+ T cells in the CLN. On the basis of these findings, we believe that CCR7 expressed CD8α−CD11c+ cells ferry Ag in the s.l. mucosa, migrate into the CLN, and share the Ag with resident CD8α+CD11c+ cells for the initiation of Ag-specific T and B cell responses following s.l. challenge. We propose that the s.l. mucosa is one of the effective mucosal inductive sites regulated by the CCR7-CCL19/CCL21 pathway.
The Role of Intrapulmonary De Novo Lymphoid Tissue in Obliterative Bronchiolitis after Lung Transplantation
Authors: Sato Masaaki , Hirayama Shin , Hwang David M. , Lara-Guerra Humberto , Wagnetz Dirk , Waddell Thomas K. , Liu Mingyao , Keshavjee Shaf
Published: May 2009

Chronic rejection after lung transplantation is manifested as obliterative bronchiolitis (OB). The development of de novo lymphoid tissue (lymphoid neogenesis) may contribute to local immune responses in small airways. Compared with normal lungs, the lung tissue of 13 lung transplant recipients who developed OB demonstrated a significantly larger number of small, airway-associated, peripheral node addressin-positive (PNAd+) high endothelial venules (HEVs) unique to lymphoid tissue (p < 0.001). HEVs were most abundant in lesions of lymphocytic bronchiolitis and “active” OB infiltrated by lymphocytes compared with those of “inactive” OB. T cells in lymphocytic bronchiolitis and active OB were predominantly of the CD45RO+CCR7− effector memory phenotype. Similar lymphoid tissue was also observed in the rat lung after intrapulmonary transplantation of allograft trachea (Brown Norway (BN) to Lewis), but not after isograft transplantation. Subsequent orthotopic transplantation of the recipient Lewis lung containing a BN trachea into an F1 (Lewis × BN) rat demonstrated stable homing of Lewis-derived T cells in the lung and their Ag-specific effector function against the secondary intrapulmonary BN trachea. In conclusion, we found de novo lymphoid tissue in the lung composed of effector memory T cells and HEVs but lacking delineated T cell and B cell zones. This de novo lymphoid tissue may play a critical role in chronic local immune responses after lung transplantation.
Airway Delivery of Silica Increases Susceptibility to Mycobacterial Infection in Mice: Potential Role of Repopulating Macrophages
Authors: Pasula Rajamouli , Britigan Bradley E. , Turner Joanne , Martin William J.
Published: May 2009

Silica exposure results in an increased lifelong risk of developing mycobacterial pulmonary infections. To date, there are no animal models that replicate this finding to permit assessment of the mechanisms underlying susceptibility to mycobacterial infection. To test the hypothesis that prior silica exposure increases risk of mycobacterial infection, we intratracheally (I.T.) administered silica, a control dust (Al2O3) or saline into mechanically ventilated C57BL/6 mice. Later, the mice received Mycobacterium avium or Mycobacterium tuberculosis I.T. Mice were sacrificed at defined time points and mycobacteria in lung homogenates were quantified. M. avium or M. tuberculosis infection was markedly increased in silica-exposed mice compared with mice exposed to either Al2O3 or saline beginning 3 wk after silica exposure. Similarly, lung sections from silica-exposed mice had many more acid fast bacilli+ (AFB+) organisms than from control mice. Alveolar macrophages (AMs) from bronchoalveolar lavage of silica-exposed mice also revealed a higher number of mycobacteria compared with mice treated with Al2O3 or saline. In addition, passive transfer of AMs from silica-exposed mice to control mice increased M. tuberculosis susceptibility. These results indicate that silica exposure converts mycobacteria-resistant mice into mycobacteria-susceptible mice via a process that likely involves a new population of AMs that are more susceptible to mycobacterial infection.
Generation of T Cells from Human Embryonic Stem Cell-Derived Hematopoietic Zones
Authors: Timmermans Frank , Velghe Imke , Vanwalleghem Lieve , De Smedt Magda , Van Coppernolle Stefanie , Taghon Tom , Moore Harry D. , Leclercq Georges , Langerak Anton W. , Kerre Tessa , Plum Jean , Vandekerckhove Bart
Published: May 2009

Human embryonic stem cells (hESC) are pluripotent stem cells. A major challenge in the field of hESC is the establishment of specific differentiation protocols that drives hESC down a particular lineage fate. So far, attempts to generate T cells from hESC in vitro were unsuccessful. In this study, we show that T cells can be generated in vitro from hESC-derived hematopoietic precursor cells present in hematopoietic zones (HZs). These zones are morphologically similar to blood islands during embryonic development, and are formed when hESC are cultured on OP9 stromal cells. Upon subsequent transfer of these HZs on OP9 cells expressing high levels of Delta-like 1 and in the presence of growth factors, cells expand and differentiate to T cells. Furthermore, we show that T cells derive exclusively from a CD34highCD43low population, further substantiating the notion that hESC-derived CD34highCD43low cells are formed in HZs and are the only population containing multipotent hematopoietic precursor cells. Differentiation to T cells sequentially passes through the physiological intermediates: CD34+CD7+ T/NK committed, CD7+CD4+CD8− immature single positive, CD4+CD8+ double positive, and finally CD3+CD1−CD27+ mature T cell stages. TCRαβ+ and TCRγδ+ T cells are generated. Mature T cells are polyclonal, proliferate, and secrete cytokines in response to mitogens. This protocol for the de novo generation of T cells from hESC could be clinically and scientifically relevant.
The Golgi-Associated Protein p115 Mediates the Secretion of Macrophage Migration Inhibitory Factor
Authors: Merk Melanie , Baugh John , Zierow Swen , Leng Lin , Pal Utpal , Lee Seung Joon , Ebert Antje D. , Mizue Yuka , Trent John O. , Mitchell Robert , Nickel Walter , Kavathas Paula B. , Bernhagen Jürgen , Bucala Richard
Published: May 2009

Macrophage migration inhibitory factor (MIF) is a leaderless protein that is secreted from cells by a specialized, nonclassical export pathway. The release of MIF nevertheless is regulated and its production in response to different inflammatory, mitogenic, and hormonal stimuli plays an important role in diverse physiologic and pathologic processes. We report herein the identification of the Golgi complex-associated protein p115 as an intracellular binding partner for MIF. MIF interacts with p115 in the cytoplasm and the stimulated secretion of MIF results in the accumulation of both proteins in supernatants, which is consistent with MIF release from cells in conjunction with p115. The depletion of p115 from monocytes/macrophages decreases the release of MIF but not other cytokines following inflammatory stimulation or intracellular bacterial infection. Notably, the small molecule MIF inhibitor 4-iodo-6-phenylpyrimidine inhibits MIF secretion by targeting the interaction between MIF and p115. These data reveal p115 to be a critical intermediary component in the regulated secretion of MIF from monocytes/macrophages.
Cutting Edge: CD28 Engagement Releases Antigen-Activated Invariant NKT Cells from the Inhibitory Effects of PD-1
Authors: Wang Jianxiong , Cheng Lu , Wondimu Zenebech , Swain Mark , Santamaria Pere , Yang Yang
Published: May 2009

Costimulatory and coinhibitory signals are important for the maintenance of immune homeostasis both in the steady state and during immune responses. In this study, we explore the relative contributions of these signals to the rapid production of large amounts of cytokines by activated invariant NKT cells (iNKT cells). We find that upon antigenic stimulation, iNKT cells rapidly up-regulate programmed death (PD)-1 and induce high levels of PD ligand 1 and costimulatory molecules on the surface of cognate Ag-presenting dendritic cells and that iNKT cells require a CD28 signal to secrete cytokines in the presence of a PD-1/PD ligand 1 interaction. CD28-deficient iNKT cells synthesized but failed to secrete cytokines during activation, and blockade of the PD-1 pathway restored the ability of CD28-deficient iNKT cells to secrete cytokines. The opposing functions of CD28 and PD-1 thus tightly regulate the unique effector function iNKT cells.