bluuebunny/crossref_metadata_2025 huggingface dataset:
Design of a Sensor Based on Plastic Optical Fibre (POF) to Measure Fluid Flow and Turbidity
Authors: Aiestaran Pedro , Arrue Jon , Zubia Joseba
Published: May 2009

Although many optical fibre applications are based on their capacity to transmit optical signals with low losses, it can also be desirable for the optical fibre to be strongly affected by a certain physical parameter in the environment. In this way, it can be used as a sensor for this parameter. There are many strong arguments for the use of POFs as sensors. In addition to being easy to handle and low cost, they demonstrate advantages common to all multimode optical fibres. These specifically include flexibility, small size, good electromagnetic compatibility behaviour, and in general, the possibility of measuring any phenomenon without physically interacting with it. In this paper, a sensor based on POF is designed and analysed with the aim of measuring the volume and turbidity of a low viscosity fluid, in this case water, as it passes through a pipe. A comparative study with a commercial sensor is provided to validate the proven flow measurement. Likewise, turbidity is measured using different colour dyes. Finally, this paper will present the most significant results and conclusions from all the tests which are carried out.
Water availability affects extracellular hydrolytic enzyme production by Aspergillus flavus and Aspergillus parasiticus
Authors: Alam S. , Shah H. , Magan N.
Published: May 2009

The objectives of this study were to examine the effect of different water activities (aw; 0.99, 0.96 and 0.94) and time (up to 120 h) on quantitative and specific enzyme production during germination and initial growth of Aspergillus flavus and A. parasiticus strains at 25 °C. This is an important early indicator of potential for aflatoxin production under conducive conditions. Qualitative API ZYM generic enzyme strips were used to identify key hydrolytic enzymes produced. Subsequently, the temporal effects of aw on the total/specific activity of the key 4-5 hydrolytic enzymes were determined using 4-nitrophenyl substrates in a 96-well microtitre plate assay. The main enzymes produced by germinating conidia of A. flavus were esterase, lipase, acid phosphatase, β-glucosidase and N-acetyl-β-D-glucosaminidase, while for A. parasiticus these were alkaline phosphatase, lipase, acid phosphatase and β-fucosidase for both total (µmol 4-nitrophenol/min/g) and specific activity (nmol 4-nitrophenol/min/µg protein). There were significant increases in the specific activity of all these enzymes of germinating spores of A. flavus (0-120 h) except for β-glucosidase which was maximum at 72 h. The total/specific activities of the enzymes produced by A. flavus were maximum at 0.99 aw, with the exception of acid phosphatase and N-acetyl-β-D-glucosaminidase at 0.94 aw. For A. parasiticus, maximum total activity occurred at 0.99 aw for fucosidase activity, while specific activity was found to be higher at lower aw levels. These enzymes are important in early colonisation of food matrices by these species and single factors (aw, time) and two-way interactions were all statistically significant for the enzymes assayed for both species. These enzymes could be used as an early and rapid indicator of the activity of Aspergillus section flavi species and suggests that rapid infection may occur over a wide range of aw conditions.
Alternaria toxins and plant diseases: an overview of origin, occurrence and risks
Authors: Logrieco A. , Moretti A. , Solfrizzo M.
Published: May 2009

The genus Alternaria includes both plant-pathogenic and saprophytic species, which may affect crops in the field
or cause harvest and postharvest decay of plant products. The taxonomy of the genus Alternaria is not well-defined
yet. A polyphasic approach based on morphological features, phylogeny and toxin profiles could be the key to a
correct identification at species level and the evaluation of mycotoxin risks associated with fungal contamination.
Species of Alternaria are known to produce many metabolites, mostly phytotoxins, which play an important role in
the pathogenesis of plants. However, certain species, in particular the most common one A. alternata, are capable
of producing several mycotoxins in infected plants and/or in agricultural commodities. The major Alternaria
mycotoxins belong to three structural classes: the tetramic acid derivative, tenuazonic acid; the dibenzopyrone
derivatives, alternariol, alternariol monomethyl ether and altenuene; and the perylene derivatives, the altertoxins.
The toxic effects of the Alternaria toxins have not yet received the same attention as the biological activities of other
mycotoxins. However, the Alternaria mycotoxins should not be underestimated since they are produced by several
Alternaria species frequently associated with a wide range of diseases in many plants of a high agrifood value. The
major problems associated with Alternaria mycotoxin contamination of agricultural products are illustrated by
focusing on various crops and their relevant diseases, e.g. black rot of tomato, olive, and carrots; black and grey rot
of citrus fruits; black point of small-grain cereals; and Alternaria diseases of apples.
El acceso al agua como factor de identificación de problemas de desarrollo agrario sostenible en el territorio del Alto Guadiana
Authors: Ruiz Pulpón Ángel Raúl
Published: May 2009

La apropiación de derechos privados sobre el uso del agua se debe a factores de tipo histórico y económico, siendo delimitados y reconocidos tras la aplicación de la legislación vigente a finales del siglo XX. La comprensión de las consecuencias sociales y económicas que se derivan permite establecer marcos de referencia globales para el enjuiciamiento del problema ambiental que se plantea en territorios con problemas de desarrollo agrario sostenible, tal y como ha ocurrido con la cuenca alta del Guadiana.
Desarrollo territorial policéntrico y ciudades intermedias: recursos productivos y dinámicas económicas locales en Andalucía
Authors: Méndez Ricardo , Melero Ana , Calatrava Ascensión
Published: May 2009

En el actual proceso de globalización y ampliación de la Unión Europea se observa una multiplicación de las formas de expresión de los territorios. Paralelamente a una progresiva concentración espacial de los recursos estratégicos y del poder, se está produciendo un proceso de descentralización en el interior de muchos países a través de un desarrollo policéntrico en el que las redes de ciudades contribuyen a favorecer la cohesión territorial y donde las ciudades intermedias están adquiriendo un protagonismo creciente. En este artículo se hace una presentación panorámica de los retos actuales que deben afrontar esas ciudades intermedias, de tamaño pequeño y medio, y de los factores de impulso capaces de dinamizarlas, fijando la atención en la selección de indicadores adecuados, especialmente en los que se centran en la realidad económica, que sirven para definir su situación actual y evolución reciente y finalizando con un análisis empírico que aplica lo anterior a una realidad concreta. El análisis empírico se realiza para las ciudades de Andalucía con el objetivo de conocer cómo afecta a la capacidad económica de las mismas la utilización de sus recursos productivos, elaborando para ello diversos índices sintéticos mediante un análisis estadístico multivariante y estableciendo una tipología de las ciudades intermedias andaluzas que intenta sintetizar las trayectorias y los comportamientos observados.
Olas de calor e influencia urbana en Madrid y su área metropolitana
Authors: Fernández García F. , Rasilla Álvarez D.
Published: May 2009

La frecuencia y duración de los episodios cálidos extremos, un fenómeno habitual en el clima mediterráneo continental de la Meseta Meridional, ha aumentado en el área de Madrid desde los años noventa, aunque su magnitud permanece constante. En el interior de la aglomeración urbana, el efecto general de la ciudad sobre estos eventos climáticos extremos ha supuesto una exacerbación del calor, no tanto por un aumento de la temperatura máxima, como por una persistencia del calor en las horas nocturnas. No obstante, la diversidad de la morfología urbana introduce variaciones espaciales en la intensidad de este calor nocturno, agravando sus efectos en las áreas densamente urbanizadas y mitigándolos en las proximidades de las áreas verdes.
Una aproximación a la caracterización climática de un sector de la montaña central cantábrica
Authors: Allende Álvarez Fernando
Published: May 2009

Una aproximación a la caracterización climática de un sector de la montaña central cantábrica. Se plantea una caracterización climática de un conjunto de macizos incluidos en la montaña central cantábrica. Como punto de partida se utilizan los datos térmicos y pluviométricos normalizados (39 y 38 estaciones respectivamente) obtenidos del SIGA (Servicio de Información Geográfico Agrario) y los de 25 pértigas de medición de espesor nival (Programa EHRIN). La información se trató mediante técnicas estadísticas de análisis multivariado y de análisis cluster con el fin de modelizar espacialmente los resultados mediante un sistema de información geográfica. En el trabajo se analizan las diferentes variables que intervienen, su validez y su relación con los elementos que resultaron determinantes en su explicación: altitud, latitud, longitud, orientación, pendiente o distancia a la divisoria de aguas y al mar.
Current importance of oleochemistry in the industrial sector of surfactants.
Authors: Gómez Herrera Carlos
Published: May 2009

Oleochemistry is an industrial sector with various applications and important developments in the field of surfactans. In this article different parts are dedicated to: A) Sources of oleochemical raw materials; B) Valorization of the oleochemistry in the field of surfactants; C) Hydrophilic heads based on carbohydrates or proteins, D) Examples of surfactants currently prepared at industrial scale, such as esters of polyols, alkylpolyglucosides, glucamides and lipoaminoacids. Collaboration between industrial sectors of surfactants and oleaginous products has evidenced various strong points. Ecological, energetic, economical and sanitary reasons will probably increase this collaboration in the future.
Chemical composition of olive oils from Arbequina and Empeltre varieties grown in irrigation
Authors: Gracia Mª Soledad , Royo Antonio , Guillén Mónica
Published: May 2009

This study examines the composition of oils extracted from young olive trees of the Arbequina and Empeltre varieties grown with irrigation in the same farm throughout a period of three seasons. Quality parameters, Fatty acid composition, sterols, waxes and aliphatic alcohols were analyzed. Although the quality of oils of both varieties was that of extra virgin, varietal differences were found. The peroxide value and the content of total polyphenols were much higher in Empeltre, whereas stability was higher in Arbequina. The monounsaturated acids were higher in Arbequina containing more stearic, oleic, arachidic and behenic acids than Empeltre, while this variety surpassed Arbequina in palmitic, margaroleic, linoleic, linolenic, gadoleic and lignoceric acids. The sterol composition was also different in the two varieties with higher contents of 24-methylencholesterol, campesterol and, especially, Δ-5 avenasterol in Arbequina, and campestanol, Δ-7 stigmastenol, Δ-7 Avenasterol in Empeltre. The contents of both waxes and aliphatic alcohols were higher in Arbequina.
Evaluation of α-tocopherol in virgin olive oil by a luminescent method
Authors: Escuderos M. E. , Sayago A. , Morales M. T. , Aparicio R.
Published: May 2009

Natural fluorophores such as tocopherols are of great importance for the characterization and authentication of virgin olive oil. The band of the luminescent spectrum which is most accurately associated with the presence of α- tocopherol (380-420 nm) at λexc = 350 nm was detected and its precision was evaluated once the analytical process was optimized. A virgin olive oil, cv. Cornicabra, was spiked with several quantities of α-tocopherol, from 25 mg/Kg to 1200mg/Kg, to build a ridge regression model (adjusted-R2 = 0.99) based on five wavelengths (370, 371, 378, 414 and 417 nm) which are attributed to the fluorescence of this compound. The tentative model was validated (adjusted-R2 = 0.87) with 8 samples of a virgin olive oil, cv. Picual, spiked with amounts of -tocopherols ranging from 25 mg/kg to 250mg/kg. Finally, the model was successfully validated with 7 monovarietal virgin olive oils from various olive producing countries (adjusted - R2 = 0.92).
Acid activation of Bentonite for use as a vegetable oil bleaching agent
Authors: Makhoukhi B. , Didi M. A. , Villemin D. , Azzouz A.
Published: May 2009

The design of various experiments in order to assess and simulate the effects of the acid activation of an Algerian bentonite on the bleaching capacity of Colza oil is described. Three key parameters of the acidic activation, namely acid concentration, contact time and temperature, were considered. The calculations made indicated that all variables display advantageous effects up to a certain level on the effectiveness of bleaching, regarded as the responsefunction. The acid concentration exerts a predominant individual effect as compared to the other parameters. Some small interactions between parameters were considered. High bleaching capacity reached 99% as optimal activation. Under accurate statistical measurements, synergy phenomena could be observed. Excessive activation is discussed in terms of loss in both porosity and acid strength.
Actividad sociocognitiva y contextos postfordistas
Authors: Quintana Castelló Francisco
Published: May 2009

En el capitalismo contemporáneo la actividad económica productiva se metamorfosea para configurar un paisaje híbrido, mezcla de modalidades avanzadas basadas en la microelectrónica y el lenguaje, postfordistas, y componentes tecno-organizativos y contractuales, algunos de los cuales evocan el factory system manchesteriano. Estos cambios comportan una profunda transformación del trabajo y de los sistemas técnicos y organizativos, perfectamente diferenciados de los que aparecen definidos por las tesis “endógenas” (versión smithiana y ley de Kaldor). En los nuevos prototipos, que recurren a sistemas automáticos y telemáticos y a formas de productivas relacionales, cognitivas y lingüísticas, el conocimiento se erige en fuerza productiva de primer orden. Un conocimiento, sin embargo, que se nutre sobre todo de un entorno innovador y del saber social sistémico y no sistémico. No obstante, esto conlleva también el surgimiento de nuevas problemáticas entre las que destaca el carácter dicotómico de algunos de los procesos generadores de conocimiento valorizante en un contexto global determinado por la lógica del activo.
Voto estructural, racional y mediatizado en las elecciones generales españolas de 1996, 2000 y 2004
Authors: González Juan Jesús
Published: May 2009

El artículo presenta tres modelos de voto que pretenden explicar aquello que cada una de las tres últimas elecciones generales celebradas en España tiene de específico. Así, se propone un modelo estructural para las elecciones de 1996, un modelo racional-económico para las elecciones de 2000 y un modelo mediatizado para explicar los mecanismos que intervinieron en las elecciones de 2004. El artículo presenta por último un modelo de voto que pretende integrar las principales conclusiones extraídas de cada uno de los modelos anteriores. Se hace especial énfasis en los mecanismos comunicativos de las últimas elecciones (2004), subrayando la influencia de los medios sobre la atribución de responsabilidad en virtud de la cual los votantes evalúan las políticas públicas, al tiempo que se llama la atención sobre el papel activo de las audiencias a la hora de seleccionar aquellos mensajes que son coherentes con su experiencia personal y con su patrón cultural.
La neorruralidad y sus significados. El caso de Navarra
Authors: Rivera María Jesús
Published: May 2009

El presente artículo tiene como objetivo indagar en los significados que se esconden tras el concepto paraguas de neorruralidad. El cambio residencial de la ciudad al campo es concebido aquí no sólo como un cambio de vivienda, sino como una apuesta vital en la que confluyen una serie de representaciones sociales sobre lo rural y lo urbano, sobre la vida en el pueblo y la vida en la ciudad. En el caso de quienes abandonaron Pamplona e instalaron su hogar en un pueblo de Navarra, estas representaciones y la heterogeneidad de expectativas de futuro subyacentes conforman tres tipos de neorruralidad diferentes que representan, a su vez, distintos modos de construir espacios rurales (y ruralidades) diferenciados, más o menos divergentes. A través del discurso expresado en una serie de entrevistas en profundidad, realizadas a personas que se autoidentificaban como migrantes urbano-rurales, exploramos estos tres tipos de neorruralidad y el sentido que esta apuesta residencial tuvo para sus protagonistas.
El Ser y el Querer Ser de la sociología analítica
Authors: Durán María de los Ángeles
Published: May 2009

No disponible.
La sociología analítica es una magnífica opción, pero no una panacea
Authors: Fernández Enguita Mariano
Published: May 2009

No disponible.
Cloning, Expression, and Mapping of Allergenic Determinants of αS1-Casein, a Major Cow’s Milk Allergen
Authors: Schulmeister Ulrike , Hochwallner Heidrun , Swoboda Ines , Focke-Tejkl Margarete , Geller Beate , Nystrand Mats , Härlin Annika , Thalhamer Josef , Scheiblhofer Sandra , Keller Walter , Niggemann Bodo , Quirce Santiago , Ebner Christoph , Mari Adriano , Pauli Gabrielle , Herz Udo , Valenta Rudolf , Spitzauer Susanne
Published: May 2009

Milk is one of the first components introduced into human diet. It also represents one of the first allergen sources, which induces IgE-mediated allergies in childhood ranging from gastrointestinal, skin, and respiratory manifestations to severe life-threatening manifestations, such as anaphylaxis. Here we isolated a cDNA coding for a major cow’s milk allergen, αS1-casein, from a bovine mammary gland cDNA library with allergic patients’ IgE Abs. Recombinant αS1-casein was expressed in Escherichia coli, purified, and characterized by circular dichroism as a folded protein. IgE epitopes of αS1-casein were determined with recombinant fragments and synthetic peptides spanning the αS1-casein sequence using microarrayed components and sera from 66 cow’s milk-sensitized patients. The allergenic activity of rαS1-casein and the αS1-casein-derived peptides was determined using rat basophil leukemia cells transfected with human FcεRI, which had been loaded with the patients’ serum IgE. Our results demonstrate that rαS1-casein as well as αS1-casein-derived peptides exhibit IgE reactivity, but mainly the intact rαS1-casein induced strong basophil degranulation. These results suggest that primarily intact αS1-casein or larger IgE-reactive portions thereof are responsible for IgE-mediated symptoms of food allergy. Recombinant αS1-casein as well as αS1-casein-derived peptides may be used in clinical studies to further explore pathomechanisms of food allergy as well as for the development of new diagnostic and therapeutic strategies for milk allergy.
Langerhans Cell Maturation and Contact Hypersensitivity Are Impaired in Aryl Hydrocarbon Receptor-Null Mice
Authors: Jux Bettina , Kadow Stephanie , Esser Charlotte
Published: May 2009

Langerhans cells (LC) are professional APCs of the epidermis. Recently, it was suggested that they are tolerogenic and control adverse immune reactions, including against low molecular mass chemicals. The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, is involved in low molecular mass chemical metabolism and cell differentiation. Growing evidence suggests a role for the AhR in the immune system, for example, by influencing dendritic cell and T cell differentiation. We found that the AhR and its repressor AhRR are expressed in LC of C57BL/6 mice. LC, unexpectedly, did not respond to a strong AhR agonist with induction of transcripts of xenobiotic metabolizing enzymes. To test for a physiological role of the AhR in LC, we investigated how AhR deficiency affects LC. We found that AhR-deficient LC were impaired in maturation; they remained smaller and less granular, did not up-regulate expression of costimulatory molecules CD40, CD80, and CD24a during in vitro maturation, and their phagocytic capacity was higher. Interestingly, the mRNA expression of tolerogenic Ido was severely decreased in AhR-deficient LC, and enzyme activity could not be induced in AhR-deficient bone marrow-derived dendritic cells. GM-CSF, needed for LC maturation, was secreted in significantly lower amounts by AhR-deficient epidermal cells. Congruent with this impaired maturity and capacity to mature, mice mounted significantly weaker contact hypersensitivity against FITC. Our data suggest that the AhR is involved in LC maturation, both cell autonomously and through bystander cells. At the same time, the AhR might be part of the risk strategy of LC against unwanted immune activation by potential skin allergens.
Tumoricidal Effects of Activated Macrophages in a Mouse Model of Chronic Lymphocytic Leukemia
Authors: Wu Qing-Li , Buhtoiarov Ilia N. , Sondel Paul M. , Rakhmilevich Alexander L. , Ranheim Erik A.
Published: May 2009

The Eμ-TCL1 transgenic mouse spontaneously develops a CD5+ B cell lymphoproliferative disorder similar to human chronic lymphocytic leukemia (CLL). Given the ineffectual T cell antitumor responses in this mouse model of CLL, we sought to determine whether combined treatment with anti-CD40 mAb (αCD40) and CpG-containing oligodeoxynucleotides (CpG) could exert immunotherapeutic effects. We have previously shown that macrophages activated by sequential ligation of CD40 and TLR9 could become cytotoxic against solid tumor cell lines both in vitro and in vivo. In the current study, we find that αCD40 plus CpG-activated macrophages induce tumor B cell apoptosis in vitro and that αCD40 plus CpG treatment markedly retards tumor growth in immunodeficient SCID/Beige mice following transplantation of primary tumor B cells. Our results suggest a novel immunotherapeutic strategy for CLL that may be effective even in the face of tumor or chemotherapy-induced T cell immunodeficiency.
Multiple Mechanisms Contribute to Impairment of Type 1 Interferon Production during Chronic Lymphocytic Choriomeningitis Virus Infection of Mice
Authors: Lee Lian Ni , Burke Shannon , Montoya Maria , Borrow Persephone
Published: May 2009

Type 1 IFNs, innate cytokines with important effector and immunomodulatory properties, are rapidly induced in the acute phase of many virus infections; however, this is generally a transient response that is not sustained during virus persistence. To gain insight into mechanisms that can contribute to down-regulation of type 1 IFN production during virus persistence, we analyzed type 1 IFN production during acute and chronic lymphocytic choriomeningitis virus (LCMV) infection. High-level type 1 IFN production was transiently up-regulated in cells including plasmacytoid and conventional dendritic cells (DCs) following LCMV infection of mice, but LCMV persistence was associated with only low-level type 1 IFN production. Nonetheless, chronically infected mice were able to up-regulate type 1 IFN production in response to TLR3, 7, and 9 ligands, albeit less efficiently than uninfected mice. Splenic DC numbers in mice chronically infected with LCMV were decreased, and the remaining cells exhibited a reduced response to TLR stimulation. LCMV-infected cell lines efficiently up-regulated type 1 IFN production following TLR ligation and infection with a DNA virus, but exhibited a defect in type 1 IFN induction following infection with Sendai, an RNA virus. This block in type 1 IFN production by infected cells, together with abnormalities in DC numbers and functions, likely contribute to the low-level type 1 IFN production in mice chronically infected with LCMV. Impairment of type 1 IFN production may both promote virus persistence and impact on host immunocompetence. Understanding the mechanisms involved may assist in development of strategies for control of virus persistence and superinfection.
Differential Role for c-Rel and C/EBPβ/δ in TLR-Mediated Induction of Proinflammatory Cytokines
Authors: Lu Yong-Chen , Kim Ira , Lye Elizabeth , Shen Fang , Suzuki Nobutaka , Suzuki Shinobu , Gerondakis Steve , Akira Shizuo , Gaffen Sarah L. , Yeh Wen-Chen , Ohashi Pamela S.
Published: May 2009

TLR stimulation triggers a signaling pathway via MyD88 and IL-1R-associated kinase 4 that is essential for proinflammatory cytokine induction. Although NF-κB has been shown to be one of the key transcriptional regulators of these cytokines, evidence suggests that other factors may also be important. In this study, we showed that MyD88-deficient macrophages have defective c-Rel activation, which has been linked to IL-12p40 induction, but not IL-6 or TNF-α. We also investigated other transcription factors and showed that C/EBPβ and C/EBPδ expression was limited in MyD88- or IL-1R-associated kinase 4-deficient macrophages treated with LPS. Importantly, the absence of both C/EBPβ and C/EBPδ resulted in the impaired induction of proinflammatory cytokines stimulated by several TLR ligands. Our results identify c-Rel and C/EBPβ/δ as important transcription factors in a MyD88-dependent pathway that regulate the induction of proinflammatory cytokines.
Selection of Molecular Structure and Delivery of RNA Oligonucleotides to Activate TLR7 versus TLR8 and to Induce High Amounts of IL-12p70 in Primary Human Monocytes
Authors: Ablasser Andrea , Poeck Hendrik , Anz David , Berger Michael , Schlee Martin , Kim Sarah , Bourquin Carole , Goutagny Nadege , Jiang Zhaozhao , Fitzgerald Katherine A. , Rothenfusser Simon , Endres Stefan , Hartmann Gunther , Hornung Veit
Published: May 2009

Detection of non-self RNA by TLRs within endosomes and by retinoic acid-inducible gene I (RIG-I)-like helicases in the cytosol is central to mammalian antiviral immunity. In this study, we used pathway-specific agonists and targeted delivery to address RNA immunorecognition in primary human immune cells. Within PBMC, plasmacytoid dendritic cells (pDC) and monocytes were found to be responsible for IFN-α production upon immunorecognition of RNA. The mechanisms of RNA recognition in pDC and monocytes were distinct. In pDC, recognition of ssRNA and dsRNA oligonucleotides was TLR7-dependent, whereas a 5′ triphosphate moiety (RIG-I ligand activity) had no major contribution to IFN-α production. In monocytes, the response to RNA oligonucleotides was mediated by either TLR8 or RIG-I. TLR8 was responsible for IL-12 induction upon endosomal delivery of ssRNA oligonucleotides and RIG-I was responsible for IFN-α production upon delivery of 5′ triphosphate RNA into the cytosol. In conclusion, the dissection of these pathways by selecting the appropriate structure and delivery of RNA reveals pDC as major producer of IFN-α upon TLR-mediated stimulation and monocytes as major producer of IFN-α upon RIG-I-mediated stimulation. Furthermore, our results uncover the potential of monocytes to function as major producers of IL-12p70, a key Th1 cytokine classically ascribed to myeloid dendritic cells that cannot be induced by CpG oligonucleotides in the human system.
Cutting Edge: TCR Stimulation Is Sufficient for Induction of Foxp3 Expression in the Absence of DNA Methyltransferase 1
Authors: Josefowicz Steven Z. , Wilson Christopher B. , Rudensky Alexander Y.
Published: May 2009

TCR signaling is important for regulatory T cell (Tr) development. Using a genetic model of DNA methyltransferase 1 (Dnmt1) deficiency, we observed highly efficient Foxp3 induction following TCR stimulation, suggesting a dominant role for TCR signaling in Foxp3 induction. In the absence of Dnmt1, Foxp3 induction in thymic and peripheral Foxp3-negative T cells was maximized upon TCR engagement, and the provision of TGF-β was dispensable for Foxp3 expression. In addition, CD4-Cre × dnmt1fl/fl mice harbored sizeable thymic and peripheral populations of CD8+Foxp3+ cells, suggesting that Dnmt1 activity is required for restricting Foxp3 expression to the CD4 T cell lineage. Our results suggest that the TCR signal is sufficient for transcriptional activation of Foxp3 in the absence of maintenance DNA methylation and that TGF-β facilitates Foxp3 induction in part by opposing cell cycle-dependent Dnmt1 recruitment, leading to locus inactivation.
Teleost B7 Expressed on Monocytes Regulates T Cell Responses
Authors: Sugamata Ryuichi , Suetake Hiroaki , Kikuchi Kiyoshi , Suzuki Yuzuru
Published: May 2009

In mammals, professional APCs induce adaptive immunity via the activation of T cells. During this process, B7 family molecules present upon APCs are known to play crucial roles in optimal T cell stimulation. In contrast, the confirmation of APCs in a nonmammalian vertebrate has yet to be achieved. To obtain further insights into the evolutionary origin of APCs, we have identified three members of the B7 family in the teleost Takifugu rubripes (fugu): B7-H1/DC, B7-H3, and B7-H4. The three fugu B7s were expressed on the surface of blood monocytes. The B7+ monocytes, which are composed of at least two distinct populations, expressed the MHC class II component gene. The fugu B7 molecules bound to activated T cells, indicating that putative B7 receptors were expressed upon T cells. Fugu B7-H1/DC inhibited T cell proliferation concomitant with increasing levels of both IL-10 and IFN-γ expression, whereas both B7-H3 and B7-H4 promoted T cell growth following IL-2 induction and the suppression of IL-10. These observations indicate that fugu B7s regulate T cell responses via receptors upon T cells. We suggest that fish B7+ monocytes are APCs and that a costimulatory system has already developed in fish via the evolutionary process.
Recombinant Soluble Human FcγR1A (CD64A) Reduces Inflammation in Murine Collagen-Induced Arthritis
Authors: Ellsworth Jeff L. , Hamacher Nels , Harder Brandon , Bannink Ken , Bukowski Thomas R. , Byrnes-Blake Kelly , Underwood Sara , Oliver Colleen , Waggie Kimberly S. , Noriega Claire , Hebb LuAnne , Rixon Mark W. , Lewis Katherine E.
Published: May 2009

Binding of immune complexes to cellular FcγRs can promote cell activation and inflammation. In previous studies, a recombinant human (rh) soluble FcγR, rh-FcγRIA (CD64A), was shown to block inflammation in passive transfer models of immune complex-mediated disease. To assess whether rh-FcγRIA could block inflammation in a T cell- and B cell-dependent model of immune complex-mediated disease, the efficacy of rh-FcγRIA in collagen-induced arthritis was evaluated. Mice with established arthritis were treated with a single s.c. injection of rh-FcγRIA (0.2–2.0 mg/dose) given every other day for 11 days. Relative to mice injected with vehicle alone, mice treated with rh-FcγRIA exhibited lower serum concentrations of IL-6, anti-type II collagen Abs, and total IgG2a. These changes were correlated with lower levels of paw swelling and joint damage in the rh-FcγRIA-treated mice and occurred in the presence of a significant murine Ab response to rh-FcγRIA. Comparison of the serum rh-FcγRIA concentration vs time profiles for rh-FcγRIA administered at two dose levels by i.v. and s.c. injection revealed that the bioavailabilty of s.c. administered rh-FcγRIA was 27–37%. Taken together, these data show that rh-FcγRIA is an effective inhibitor of inflammation in a model of established arthritis in mice.
Soluble TLR2 Is Present in Human Amniotic Fluid and Modulates the Intraamniotic Inflammatory Response to Infection
Authors: Dulay Antonette T. , Buhimschi Catalin S. , Zhao Guomao , Oliver Emily A. , Mbele Ayanda , Jing Shichu , Buhimschi Irina A.
Published: May 2009

TLRs are pattern recognition transmembrane receptors that play key roles in innate immunity. A recently discovered soluble truncated form of TLR2 (sTLR2) acts as a decoy receptor, down-regulating the host inflammatory response to bacteria. To identify the presence and functional role of sTLR2 in modulating the intraamniotic inflammatory response to infection, we studied 109 amniotic fluid samples of women with normal pregnancy outcomes (n = 28) and women with (n = 39) and without (n = 42) intraamniotic infection. We sought to demonstrate a functional role of the amniotic fluid sTLR2 in modulating the TLR2 inflammatory signaling in vitro by using a villous explant system. Two sTLR2 forms were identified, and specificity was confirmed with neutralizing peptides. We showed that sTLR2 is present constitutively in amniotic fluid, its levels are gestational age dependent, and we determined that the sTLR2 quantity and functional engagement modulates the intensity of the intraamniotic inflammation elicited by Gram-positive bacteria. In vitro, we demonstrated that challenging placental villous explants with a specific TLR2 agonist (Pam3Cys) induced a significant cytokine response. Notably, preincubation of the preterm, but not near-term, amniotic fluid with Pam3Cys significantly inhibited the ability of this TLR2 agonist to elicit a cytokine reaction. Moreover, depletion of sTLR2 from preterm amniotic fluid removed its neutralizing property. Monensin significantly diminished sTLR2 immunoreactivity, indicating that sTLR2 is the result of intracellular posttranslational processing of TLR2. We conclude that sTLR2 is part of the amniotic fluid innate immune system and participates in regulating the inflammatory response to microbial pathogens.
Macrophage Migration Inhibitory Factor Homologs of Anisakis simplex Suppress Th2 Response in Allergic Airway Inflammation Model via CD4+CD25+Foxp3+ T Cell Recruitment
Authors: Park Sang Kyun , Cho Min Kyoung , Park Hye-Kyung , Lee Keun Hee , Lee Sun Joo , Choi Seon Hee , Ock Mee Sun , Jeong Hae Jin , Lee Moo Hyung , Yu Hak Sun
Published: May 2009

We have cloned the macrophage migration inhibitory factor (MIF)-like protein (Anisakis simplex (As)-MIF) from larvae of the whale worm (Anisakis simplex third-stage larvae). Asthma was induced in the mice using OVA/alum, with or without various concentrations of rAs-MIF treatment before OVA/alum challenge. Treatment with rAs-MIF coupled with OVA/alum during the challenge period induced a complete inhibition of eosinophilia and goblet cell hyperplasia within the lung and profoundly ameliorated the development of lung hyperreactivity. Also, rAs-MIF was shown to reduce profoundly the quantity of Th2-related cytokines (IL-4, IL-5, and IL-13) in the bronchial alveolar lavage fluid and allergen-specific IgG2a in sera. IL-10 and TGF-β levels in the bronchoalveolar lavage fluid of the rAs-MIF-treated group were significantly higher than in the other groups. Additionally, CD4+CD25+Foxp3+ T cells (regulatory T) were recruited to the spleen and lungs of the rAs-MIF-treated mice, but this recruitment was inhibited by anti-rAs-MIF Ab.
Impaired NFAT Transcriptional Activity in Antigen-Stimulated CD8 T Cells Linked to Defective Phosphorylation of NFAT Transactivation Domain
Authors: Leung-Theung-Long Stéphane , Mondor Isabelle , Guiraud Martine , Lamare Camille , Nageleekar Viswas , Paulet Pierre-Emmanuel , Rincon Mercedes , Guerder Sylvie
Published: May 2009

NFAT transcription factors play critical roles in CD4 T cell activation and differentiation. Their function in CD8 T cell is, however, unknown. We show in this study that, in contrast to CD4 T cells, Ag-stimulated CD8 T cells do not demonstrate NFAT transcriptional activity despite normal regulation of NFAT nuclear shuttling. Further analysis of the signaling defect shows that phosphorylation of the 53SSPS56 motif of the NFAT transactivation domain is essential for NFAT-mediated transcription in primary T cells. Although Ag stimulation induces in CD4 T cells extensive phosphorylation of this motif, it does so only minimally in CD8 T cells. Although Ag stimulation triggers only modest activation of the p38 MAPK in CD8 T cells as opposed to CD4 T cells, p38 MAPK is not the upstream kinase that directly or indirectly phosphorylates the NFAT 53SSPS56 motif. These findings reveal an unsuspected difference between CD4 and CD8 T cells in the TCR downstream signaling pathway. Therefore, whereas in CD4 T cells TCR/CD28 engagement activates a yet unknown kinase that can phosphorylate the NFAT 53SSPS56 motif, this pathway is only minimally triggered in CD8 T cells, thus limiting NFAT transcriptional activity.
Poly(ADP-Ribose) Polymerase-1 Regulates the Progression of Autoimmune Nephritis in Males by Inducing Necrotic Cell Death and Modulating Inflammation
Authors: Jog Neelakshi R. , Dinnall Joudy-Ann , Gallucci Stefania , Madaio Michael P. , Caricchio Roberto
Published: May 2009

Necrotic lesions and necrotic cell death characterize severe autoimmune nephritides, and contribute to local inflammation and to progression of the disease. Poly(ADP-ribose) polymerase-1 (PARP-1), a DNA repair enzyme, is involved in the induction of necrosis and is a key player in the acute and chronic inflammation. Therefore, we hypothesized that PARP-1 controls the severity of nephritis by mediating the induction of necrosis in the kidney. We used lupus and anti-glomerular basement membrane models of nephritis to determine the effects of PARP-1 on the inflammatory response in the kidney. We show in this study that PARP-1 is indeed activated during the course of glomerulonephritis. We also show that the absence of PARP-1 or its pharmacological inhibition results in milder nephritis, with lower blood urea nitrogen levels, reduced necrotic lesions, and higher survival rates. The relevance of PARP-1 showed a strong male sex specificity, and treatment of male mice with 17β-estradiol prolonged their survival during the course of nephritis. PARP-1 also regulated TNF-α expression and up-regulation of adhesion molecules, further supporting a role of PARP-1 in the inflammatory process within the kidney. Our results demonstrate that PARP-1 activation and consequent necrotic cell death play an important role in the pathogenesis of male nephritis, and suggest that PARP-1 can be a novel therapeutic target in glomerulonephritis.
Kinetics of Expansion of Epitope-Specific T Cell Responses during Primary HIV-1 Infection
Authors: Turnbull Emma L. , Wong MaiLee , Wang Shuyi , Wei Xiping , Jones Nicola A. , Conrod Karen E. , Aldam Diana , Turner Jo , Pellegrino Pierre , Keele Brandon F. , Williams Ian , Shaw George M. , Borrow Persephone
Published: May 2009

Multiple lines of evidence support a role for CD8+ T cells in control of acute/early HIV replication; however, features of the primary HIV-specific CD8+ T cell response that may impact on the efficiency of containment of early viral replication remain poorly defined. In this study, we performed a novel, comprehensive analysis of the kinetics of expansion of components of the HIV-specific CD8+ T cell response in 21 acutely infected individuals. Epitope-specific T cell responses expanded asynchronously during primary infection in all subjects. The most rapidly expanded responses peaked as early as 5 days following symptomatic presentation and were typically of very limited epitope breadth. Responses of additional specificities expanded and contracted in subsequent waves, resulting in successive shifts in the epitope immunodominance hierarchy over time. Sequence variation and escape were temporally associated with the decline in magnitude of only a subset of T cell responses, suggesting that other factors such as Ag load and T cell exhaustion may play a role in driving the contraction of HIV-specific T cell responses. These observations document the preferential expansion of CD8+ T cells recognizing a subset of epitopes during the viral burst in acute HIV-1 infection and suggest that the nature of the initial, very rapidly expanded T cell response may influence the efficiency with which viral replication is contained in acute/early HIV infection.
MFG-E8 Attenuates Intestinal Inflammation in Murine Experimental Colitis by Modulating Osteopontin-Dependent αvβ3 Integrin Signaling
Authors: Aziz Md. Monowar , Ishihara Shunji , Mishima Yoshiyuki , Oshima Naoki , Moriyama Ichiro , Yuki Takafumi , Kadowaki Yasunori , Rumi Mohammad Azharul Karim , Amano Yuji , Kinoshita Yoshikazu
Published: May 2009

MFG-E8 (milk fat globule-epidermal growth factor 8) deficiency is strongly associated with acquisition of immune-mediated disorders due to the loss of tissue homeostasis. However, comparatively little is known regarding its functions in gastrointestinal tract disorders, in which immune homeostasis is a major concern. Herein, we report altered MFG-E8 expression in inflamed colons during the acute phase of murine experimental colitis and found that treatment with recombinant MFG-E8, but not its arginine-glycine-aspartate mutant counterpart, ameliorated colitis by reducing inflammation and improving disease parameters. To reveal the MFG-E8-mediated antiinflammatory mechanism, we employed an in vitro system, which showed the down-regulation of NF-κB in an LPS-dependent manner. Additionally, MFG-E8 altered αvβ3 integrin-mediated focal adhesion kinase phosphorylation by impeding the binding of one of its potent ligands osteopontin, which becomes activated during colitis. Taken together, our results indicated that MFG-E8 has a novel therapeutic potential for treatment of colitis.
PI3K Links NKG2D Signaling to a CrkL Pathway Involved in Natural Killer Cell Adhesion, Polarity, and Granule Secretion
Authors: Segovis Colin M. , Schoon Renee A. , Dick Christopher J. , Nacusi Lucas P. , Leibson Paul J. , Billadeau Daniel D.
Published: May 2009

The NK cell-activating receptor NKG2D plays a critical role in the destruction of malignant cells, but many of the cell-signaling mechanisms governing NKG2D-mediated cellular cytotoxicity are unknown. We have identified an NKG2D-mediated signaling pathway that governs both conjugate formation and cytotoxic granule polarization. We demonstrate that an interaction between the regulatory subunit of PI3K, p85, and the adaptor protein CrkL is required for efficient NKG2D-mediated cellular cytotoxicity. We show decreased NK cell-target cell conjugate formation in NK cells treated with PI3K inhibitors or depleted of CrkL. Independent of adhesion, we find that microtubule organization center polarization toward target cells expressing the NKG2D ligand MICA or toward anti-NKG2D-coated beads is impaired in the absence of CrkL. Ab-stimulated granule release is also impaired in NK cells depleted of CrkL. Furthermore, our data indicate that the small Ras family GTPase Rap1 is activated downstream of NKG2D engagement in a PI3K- and CrkL-dependent manner and is required for conjugate formation, MTOC (microtubule organizing center) polarization, and NKG2D-dependent cellular cytotoxicity. Taken together, our data identify an NKG2D-activated signaling pathway that collectively orchestrates NK cell adhesion, cell polarization, and granule release.
Costimulation Modulation Uncouples Protection from Immunopathology in Memory T Cell Responses to Influenza Virus
Authors: Teijaro John R. , Njau Modesta N. , Verhoeven David , Chandran Smita , Nadler Steven G. , Hasday Jeffrey , Farber Donna L.
Published: May 2009

The rapid effector functions and tissue heterogeneity of memory T cells facilitate protective immunity, but they can also promote immunopathology in antiviral immunity, autoimmunity, and transplantation. Modulation of memory T cells is a promising but not yet achieved strategy for inhibiting these deleterious effects. Using an influenza infection model, we demonstrate that memory CD4 T cell-driven secondary responses to influenza challenge result in improved viral clearance yet do not prevent the morbidity associated with viral infection, and they exacerbate cellular recruitment into the lung, compared with primary responses. Inhibiting CD28 costimulation with the approved immunomodulator CTLA4Ig suppressed primary responses in naive mice infected with influenza, but was remarkably curative for memory CD4 T cell-mediated secondary responses to influenza, with reduced immunopathology and enhanced recovery. We demonstrate that CTLA4Ig differentially affects lymphoid and nonlymphoid responses to influenza challenge, inhibiting proliferation and egress of lymphoid naive and memory T cells, while leaving lung-resident memory CD4 T cell responses intact. Our findings reveal the dual nature of memory T cell-mediated secondary responses and suggest costimulation modulation as a novel strategy to optimize antiviral immunity by limiting the memory T cell response to its protective capacities.
Fatty Acyl Structures of Mycobacterium tuberculosis Sulfoglycolipid Govern T Cell Response
Authors: Guiard Julie , Collmann Anthony , Garcia-Alles Luis Fernando , Mourey Lionel , Brando Thérèse , Mori Lucia , Gilleron Martine , Prandi Jacques , De Libero Gennaro , Puzo Germain
Published: May 2009

CD1b-restricted T lymphocytes recognize a large diversity of mycobacterial lipids, which differ in their hydrophilic heads and the structure of their acyl appendages. Both moieties participate in the antigenicity of lipid Ags, but the structural constraints governing binding to CD1b and generation of antigenic CD1b:lipid Ag complexes are still poorly understood. Here, we investigated the structural requirements conferring antigenicity to Mycobacterium tuberculosis sulfoglycolipid Ags using a combination of CD1b:lipid binding and T cell activation assays with both living dendritic cells and plate-bound recombinant soluble CD1b. Comparison of the antigenicity of a panel of synthetic analogs, sharing the same trehalose-sulfate polar head, but differing in the structure of their acyl tails, shows that the number of C-methyl substituents on the fatty acid, the configuration of the chiral centers, and the respective localization of the two different acyl chains on the sugar moiety govern TCR recognition and T lymphocyte activation. These studies have major implications for the design of sulfoglycolipid analogs with potential use as tuberculosis subunit vaccines.
Disruption of Nrf2 Impairs the Resolution of Hyperoxia-Induced Acute Lung Injury and Inflammation in Mice
Authors: Reddy Narsa M. , Kleeberger Steven R. , Kensler Thomas W. , Yamamoto Masayuki , Hassoun Paul M. , Reddy Sekhar P.
Published: May 2009

Aberrant tissue repair and persistent inflammation following oxidant-mediated acute lung injury (ALI) can lead to the development and progression of various pulmonary diseases, but the mechanisms underlying these processes remain unclear. Hyperoxia is widely used in the treatment of pulmonary diseases, but the effects of this oxidant exposure in patients undergoing recovery from ALI are not clearly understood. Nrf2 has emerged as a crucial transcription factor that regulates oxidant stress through the induction of several detoxifying enzymes and other proteins. Using an experimental model of hyperoxia-induced ALI, we have examined the role of oxidant stress in resolving lung injury and inflammation. We found that when exposed to sublethal (72 h) hyperoxia, Nrf2-deficient, but not wild-type mice, succumbed to death during recovery. When both genotypes were exposed to a shorter period of hyperoxia-induced ALI (48 h), the lungs of Nrf2-deficient mice during recovery exhibited persistent cellular injury, impaired alveolar and endothelial cell regeneration, and persistent cellular infiltration by macrophages and lymphocytes. Glutathione (GSH) supplementation in Nrf2-deficient mice immediately after hyperoxia remarkably restored their ability to recover from hyperoxia-induced damage in a manner similar to that of wild-type mice. Thus, the results of the present study indicate that the Nrf2-regulated transcriptional response and, particularly GSH synthesis, is critical for lung tissue repair and the resolution of inflammation in vivo and suggests that a dysfunctional Nrf2-GSH pathway may compromise these processes in vivo.