bluuebunny/crossref_metadata_2025 huggingface dataset:
Predicting Clinical Visual Acuity of Presbyopia Treatments
Authors: Schwiegerling Jim
Published: March 2010

PURPOSE:

To predict the potential clinical visual acuity of different presbyopia treatments.

METHODS:

The defocus transfer function (DTF) is a mathematical technique for simultaneously illustrating the optical transfer function for all levels of defocus. Through-focus clinical visual acuity measurements were superimposed onto the DTF to determine the corresponding retinal contrast and map out a modulation threshold curve. The process is performed for an apodized diffractive and a zonal refractive intraocular lens, as well as an opaque annular ring implant that extends depth of focus.

RESULTS:

Clinical visual acuity measurements appear to track contours on the DTF. The elevation of these contours changes as a function of spatial frequency, with the general trend being that for higher spatial frequencies, more retinal contrast is needed to achieve a given level of visual acuity. The presence of these contours suggests a minimum level of retinal contrast is needed to achieve a given visual acuity, and if this threshold is exceeded, the presbyopia treatment can provide the corresponding acuity clinically.

CONCLUSIONS:

The DTF provides a global view of ocular performance for all object distances. The disparate technologies investigated all gave similar modulation threshold curves. These results suggest that the modulation threshold curve can be used to predict potential visual acuity of other multifocal lens designs and methods for treating presbyopia. [
J Refract Surg
. 2010;26:66–70.]
Versiones cinematográficas del tema fáustico
Authors: Suárez Lafuente M. S.
Published: March 2010

La leyenda fáustica, en la que el personaje principal vende su alma al diablo por conseguir lo que más anhela en ese momento, se ha convertido, desde su primera publicación en la imprenta de Johann Spiess en 1587, en un tema recurrente en diferentes medios artísticos. En la literatura en todas sus manifestaciones, en pintura, música y cine, diferentes Faustos soñaron con el placer, el conocimiento, la fama, el dinero o el poder, y aprendieron, de manera dramática, que la vida es breve y los logros humanos efímeros. Puesto que la duda primordial de qué hay después de la muerte no puede ser satisfecha, la venta del alma se convierte en una transacción fútil o trágica, según fuera la respuesta, que ningún Fausto llega a dilucidar. Mefistófeles, el mensajero del diablo, no tiene más remedio que convertirse en un mago o en un bufón para distraer a su señor terrenal, para que no piense en temas trascendentales ni se dé cuenta de las limitaciones de su siervo. Durante cuatro siglos, los personajes de esta leyenda se han adaptado a los cambios filosóficos, sociales, políticos y económicos del mundo occidental y a su reflejo en el arte. En las últimas décadas el duelo dialéctico Fausto / Mefistófeles se ha adaptado al desarrollo de la teoría y de la ciencia en nuestra sociedad; así, encontramos feminizaciones del mito, Faustos transculturales, postmodernos y altamente tecnificados. En este artículo contemplamos su transposición al cine, mencionando las películas más significativas en el desarrollo del tema.
Clásicos y modernos: dos adaptaciones literarias de Orson Welles
Authors: Molina Foix Vicente
Published: March 2010

Se estudia la trayectoria cinematográfica de Orson Welles con especial referencia a las adaptaciones de las obras de Shakespeare y dentro de ellas Macbeth, destacando la influencia de Jacques Tourner con su obra Yo anduve con un Zombie y construyendo su obra con los parámetros del cine de terror fantástico. Se describe el interés de Wells por la obra de Isak Dinesen y su adaptación de Una historia inmortal.
El ilusionista de las palabras: Paul Auster y su universo creativo
Authors: Álvarez López Esther
Published: March 2010

Paul Auster es uno de los grandes escritores de nuestro tiempo. Desde 1994, a su labor de novelista, poeta, traductor y ensayista ha añadido la de guionista y director de cine. Ambos medios, literatura y cine, aparecen estrechamente ligados en su producción creativa, de manera que uno nutre al otro y viceversa, a través de temas y personajes comunes, de guiños autorreferenciales y metaficcionales. En novelas, relatos y películas Auster se revela, en esencia, como un gran contador de historias. Se trata de historias múltiples que se superponen a distintos niveles narrativos siguiendo la técnica de cajas chinas. Su obra forma parte de una amplia red de referencias internas y externas que dialogan entre sí, al tiempo que plantean cuestiones en torno a la identidad, la escritura o las intersecciones entre ficción y realidad, que aparecen de manera recurrente tanto en forma literaria como fílmica.
La traslación de la mirada aborigen: Generación Robada y la mediación intertextual
Authors: Carrera Suárez Isabel
Published: March 2010

Siguiendo el desarrollo reciente de los estudios sobre adaptación, que tienden a interrogar la relación intertextual entre el medio escrito y el cinematográfico, este artículo analiza la película Generación robada (Noyce, 2002), destacando la compleja intertextualidad que la compone: el libro que constituye el texto-fuente, Follow the Rabbit-Proof Fence (1996) de Doris Pilkington-Garimara; el informe Bringing Them Home (1997) sobre la separación forzada de niños aborígenes; los textos y actos políticos de la reconciliación nacional australiana y, finalmente, las biografías y la participación de las actrices aborígenes y sus comunidades. Todos ellos contribuyen a la traslación visual y la articulación de un film en el que la imbricación entre historia y arte es un elemento constitutivo.
La música popular de la literatura al cine: lenguaje, discurso y significados en Alta Fidelidad y The Commitments
Authors: Viñuela Suárez Eduardo
Published: March 2010

La adaptación cinematográfica de novelas va más allá de la transposición de la narrativa de un medio de expresión a otro e implica a una serie de discursos que están presentes en la obra y que son activados por el lector-espectador en función de su competencia cultural. La música, presente en ambos medios, es capaz de vehicular mensajes que, aunque no se encuentren en la estructura narrativa de las obras, participan en la creación de significados.
En este artículo abordamos un análisis formal y discursivo de la música popular en Alta fidelidad y The Commitments, dos novelas adaptadas al cine en las que la ideología de la cultura rock se manifiesta en personajes y espacios. Canciones, músicos e instrumentos aparecen en texto escrito, diálogos, imagen y sonido en las novelas de Roddy Doyle y Nick Hornby y sus respectivas adaptaciones cinematográficas de Alan Parker y Stephen Frears, demostrando la condición multimedia de la música como lenguaje y su capacidad para interactuar con la estructura narrativa y articular sus propios discursos de forma paralela.
Tiempo y sucesión ecológica en Ramón Margalef
Authors: Vargas Abarzúa Esteban , Zúñiga Molinier Luis
Published: March 2010

En este trabajo intentamos meditar la concepción de tiempo en la teoría de sucesión ecológica de Margalef. En un modelo clásico de sucesión ecológica, las poblaciones se suceden unas a otras. Cada fase de esa sucesión “en tanto fase temporal” está meramente yuxtapuesta a las demás fases. Es el tiempo cronométrico, el tiempo como “medida” del reloj. El tiempo es aquí algo absoluto, independiente del proceso como en Newton. Esto no ocurre en el modelo de Margalef. Él piensa el ecosistema como un proceso de transferencia de energía y acumulación de información. Por esto, en el proceso dinámico del ecosistema existen diversas fases determinadas por la dinámica intrínseca del sistema. Cada ecosistema posee así su tiempo propio.
Gypsum-induced decay in granite monuments in Northwestern Spain
Authors: Silva Hermo B. , Prieto Lamas B. , Rivas Brea T. , Pereira Pardo L.
Published: March 2010

One of the most common forms of decay in granite monuments is the detachment of the superficial layer of the stone (plaques, plaquettes and scales). Previous studies of granite monuments in the northwest Iberian Peninsula revealed a direct relation between this type of weathering and the presence of calcium sulphate, and a mechanism whereby the salt causes this type of decay was suggested. In the present study, various hypotheses as regards the origin of the gypsum found in granite monuments are proposed. The study involved analysis of the contents of ions soluble in water, the results of X-ray diffraction analyses and the ratios of CaO/SO3 in samples of stone, mortar and deposits collected from different monuments. It was concluded that in most cases the gypsum originated from old paintworks or/and from the joint mortars, although inputs from other sources cannot be discounted, as discussed
T Cell Ig and Mucin Domain Proteins and Immunity
Authors: Kane Lawrence P.
Published: March 2010

Proteins of the transmembrane (or T cell) Ig and mucin domain (TIM) family are expressed by multiple cell types within the immune systems of rodents and humans. Studies over the last several years have suggested that these proteins may be promising targets for therapeutic manipulation of immune responses. This review discusses the progress that has been made in understanding TIM protein function in the immune system, as well as some of the unresolved issues that remain on the road to eventually targeting TIM proteins for enhancing or inhibiting immunity.
Death by suicide long after electroconvulsive therapy. Is the sense of coherence test of Antonovsky a predictor of mortality from depression?
Authors: Berg John E.
Published: March 2010

Prediction of increased risk of suicide is difficult. We had the opportunity to follow up 20 patients receiving electroconvulsive therapy (ECT) because of severe depression. They filled in the Antonovsky sense of coherence test (SOC) and Beck depression inventory (BDI) before and after a series of ECT treatments. Seventeen surviving patients had a mean observation time of 20.6 months, whereas the three deceased patients had 11.3 months. There was a lower mean age at onset of illness and a longer mean duration of disease in the deceased. Other clinical parameters did not differ. The surviving patients had a significant decrease on the BDI from 35 to 18 (P<0.001) and an increase on the SOC test after ECT from 2.45 to 3.19 (P<0.001), indicating both less depression and better functioning in life. The deceased had a larger change on the BDI from 32 to 13, not attaining significance because of the low number of deceased. The SOC test, however, did not increase to a purported normal level; that is, from 2.43 to 2.87. Although the SOC scale has been shown to predict mortality in substance abusers, the SOC test has not been part of earlier reviews of predictive power. Tentatively, a low pathological score on the SOC test may indicate low sense of coherence in life that might increase the propensity for suicide. These preliminary results need replication in larger studies.
The application of holography to the analysis of size and settling velocity of suspended cohesive sediments
Authors: Graham George W. , Nimmo Smith W. Alex M.
Published: March 2010

Suspended cohesive sediments commonly occur in flocculated form. The flocculation process significantly increases particle size, settling velocity, and settling flux in comparison to unflocculated particles. To better understand suspended particles, a new instrument for in situ imaging using digital inline holography is presented and evaluated. With a resolution of 7.4 µm per pixel and a field of view of 7.4 × 7.4 mm, the instrument generates sharply focused images of particles from approximately 20 µm to 7 mm in diameter at up to 25 frames per second. A significant advantage of holography over current imaging systems is that in‐focus images are obtained over a substantial depth of field. Contained in small‐diameter cylindrical housings, the instrument presents minimal flow disruption and is easily deployable. Digitally recorded holograms are reconstructed and analyzed for number and size of particles in a fully automated manner. To assess the systems' potential, particle size distributions for two grades of quartz sand are compared with those from a laser diffraction particle sizer and are found to exhibit good similarity. To simultaneously estimate particle size and settling velocity, a modification to the system is demonstrated in which settling particles are automatically tracked and sized. The resulting relationships between settling velocity and effective density as functions of particle size are characteristic of suspended cohesive sediments and empirical power‐law descriptors of these relationships show excellent agreement with previously published studies.
In Vitro Muscarinic Receptor Radioligand‐Binding Assays
Authors: Steinfeld Tod , Pulido‐Rios M. Teresa , Armstrong Scott , Hegde Sharath S.
Published: March 2010

G‐protein‐coupled muscarinic receptors (mAChRs), of which there are five subtypes (M1‐M5), are attractive drug targets for a number of disorders. Described in this unit are radioligand‐binding assays for defining the selectivity and affinity of chemical agents at the five mAChR subtypes. Detailed methodologies and troubleshooting strategies are provided for saturation‐binding studies, to estimateKDandBmaxvalues, and for competition‐binding studies to estimateKivalues. Emphasis is placed on experimental details that are critical for executing a robust and reliable assay.Curr. Protoc. Pharmacol. 48:1.33.1‐1.33.18. © 2010 by John Wiley & Sons, Inc.
In Vitro Isolated Tissue Functional Muscarinic Receptor Assays
Authors: Pulido‐Rios M. Teresa , Steinfeld Tod , Armstrong Scott , Watson Nikki , Choppin Agnes , Eglen Richard , Hegde Sharath S.
Published: March 2010

Muscarinic receptor (mAChRs) subtypes are viable targets for the design of novel agents for use in a number of central and peripheral disorders. In vitro isolated tissue functional assays for muscarinic receptor subtypes have played an invaluable role in basic research and drug discovery. The availability of biological assays for generation of quantitative estimates of affinity and potency of ligands allows evaluation of the contribution of a given mAChR to the functional end organ response and also enables drug discovery by facilitating the iterative process of screening and optimization of chemical leads. This unit describes isolated tissue functional assays for the quantification of ligand affinity and efficacy at the M1, M2, M3, M4, and M5muscarinic receptor subtypes in tissues expressing the native receptor using organ bath techniques.Curr. Protoc. Pharmacol. 48:4.15.1‐4.15.29. © 2010 by John Wiley & Sons, Inc.
In Vitro Selection of RNA Aptamers to a Small Molecule Target
Authors: Codrea Vlad , Hayner Michelle , Hall Bradley , Jhaveri Sulay , Ellington Andrew
Published: March 2010

This unit describes the selection of aptamers from a single‐stranded RNA pool that bind to small molecule targets. Aptamers generated by this type of selection experiment can potentially function as receptors for small molecules in numerous applications, including medical diagnostics, therapeutics, and environmental monitoring. This unit describes two modes of selection, one by column filtration and one by batch selection. Curr. Protoc. Nucleic Acid Chem. 40:9.5.1‐9.5.23. © 2010 by John Wiley & Sons, Inc.
The Continuous Evolution In Vitro Technique
Authors: Arenas Carolina Díaz , Lehman Niles
Published: March 2010

In vitro experimentation techniques were developed in response to the necessity of exploring new molecular structures and functions and to better understand evolutionary phenomena that shape organismal and molecular populations. The advancement of these techniques has allowed further exploration of more complicated evolutionary dynamics. One such technique is the continuous evolution in vitro (CE) method, to which this unit is devoted. The CE method is characterized by continuous cycles of amplification of RNA molecules that occur without much participation of the researcher. This feature allows us to evolve lineages in which the evolutionary phenomena occurring at the molecular level more closely mimic what happens in organismal populations in the present, or what may have happened in RNA populations during the RNA world stage of life. Curr. Protoc. Nucleic Acid Chem. 40:9.7.1‐9.7.16. © 2010 by John Wiley & Sons, Inc.
Overview of Formation of G‐Quadruplex Structures
Authors: Sannohe Yuta , Sugiyama Hiroshi
Published: March 2010

There are many structures that can be adopted by nucleic acids other than the Watson‐Crick duplex. In particular, a noncanonical four‐stranded topology, called a G‐quadruplex, is of great interest because of its roles in key biological processes such as the maintenance of telomeres and regulation of gene transcription. This review describes the condition for forming the G‐quadruplex structure, G‐quadruplex‐forming sequences, and methods for studying the structures. Curr. Protoc. Nucleic Acid Chem. 40:17.2.1‐17.2.17. © 2010 by John Wiley & Sons, Inc.
Isolation of Amniotic Mesenchymal Stem Cells
Authors: Marongiu Fabio , Gramignoli Roberto , Sun Qian , Tahan Veysel , Miki Toshio , Dorko Kenneth , Ellis Ewa , Strom Stephen C.
Published: March 2010

Mesenchymal stem cells (MSCs) have the ability to differentiate into osteocytes, chondrocytes, and adipocytes and possess immunomodulatory properties. Amniotic membrane from human term placenta is a potential source of multipotent MSCs that could be useful for regenerative medicine. This unit describes a detailed and simple protocol for the isolation of amniotic mesenchymal cells. We also introduce a simple density separation technique for the purification of this cell type from possible contamination with amniotic epithelial cells. Curr. Protoc. Stem Cell Biol. 12:1E.5.1‐1E.5.11. © 2010 by John Wiley & Sons, Inc.
Construction and Use of Glycan Microarrays
Authors: Campbell Christopher T. , Zhang Yalong , Gildersleeve Jeffrey C.
Published: March 2010

Glycosylation is an important post‐translational modification that influences many biological processes critical for development, normal physiologic function, and diseases. Unfortunately, progress toward understanding the roles of glycans in biology has been slow due to the challenges of studying glycans and the proteins that interact with them. Glycan microarrays provide a high‐throughput approach for the rapid analysis of carbohydrate‐macromolecule interactions. Protocols detailed here are intended to help laboratories with basic familiarity of DNA or protein microarrays to begin printing and performing assays using glycan microarrays. Basic and advanced data processing are also detailed, along with strategies for improving reproducibility of data collected with glycan arrays. Curr. Protoc. Chem Biol. 2:37‐53. © 2010 by John Wiley & Sons, Inc.
Heat transfer in nanoparticle suspensions: Modeling the thermal conductivity of nanofluids
Authors: Warrier Pramod , Yuan Yanhui , Beck Michael P. , Teja Amyn S.
Published: March 2010

This work reviews experimental data and models for the thermal conductivity of nanoparticle suspensions and examines the effect of the properties of the two phases on the effective thermal conductivity of the heterogeneous system. A model is presented for the effective thermal conductivity of nanofluids that takes into account the temperature dependence of the thermal conductivities of the individual phases, as well as the size dependence of the thermal conductivity of the dispersed phase. We demonstrate that this model can be used to calculate the thermal conductivity of nanofluids over a wide range of particle sizes, particle volume fractions, and temperatures. The model can also be used to validate experimental thermal conductivity data for nanofluids containing semiconductor or insulator particles and confirm the size dependence of the thermal conductivity of nanoparticles. © 2010 American Institute of Chemical Engineers AIChE J, 2010
Directed self‐assembly by photostimulation of an amorphous semiconductor surface
Authors: Kondratenko Yevgeniy V. , Seebauer Edmund G.
Published: March 2010

A method for nanoscale directed self‐assembly is demonstrated that employs an amorphous semiconductor containing subcritical nuclei for crystallization. This strategy combines attractive features of top‐down and bottom‐up approaches by exploiting the self‐organization capabilities latent in amorphous materials, but in a way that can be controlled by optical or electron beam exposure tools. The method was demonstrated with amorphous TiO2deposited on silicon, heated to 270°C, and exposed to low‐level ultraviolet light. © 2010 American Institute of Chemical Engineers AIChE J, 2010
Predicting the phase equilibria of synthetic petroleum fluids with the PPR78 approach
Authors: Jaubert Jean‐Noël , Privat Romain , Mutelet Fabrice
Published: March 2010

The PPR78 approach is a group contribution‐based thermodynamic model which combines at constant packing fraction the Peng–Robinson equation of state and a Van Laar‐type gE model. This article demonstrates that, using classical mixing rules (linear on b and quadratic on a), the PPR78 model may also be seen as a group contribution method for the estimation of the temperature‐dependent kij of the widely used PR EoS. Our model is endowed of 15 groups and it is possible to predict the kij for any mixture containing alkanes, aromatics, naphthenes, CO2, N2, H2S, and mercaptans. This study exhibits the capability of this approach to predict the phase behavior of synthetic petroleum fluids containing components of different volatilities. The many comparisons between calculated and experimental data on natural gases, crude oils, and gas condensates allow concluding that the PPR78 approach is a successful model for phase equilibria calculations of this kind of mixtures. © 2010 American Institute of Chemical Engineers AIChE J, 2010
Dry coating of talc particles: Effect of material and process modifications on their wettability and dispersibility
Authors: Lefebvre Guillaume , Galet Laurence , Chamayou Alain
Published: March 2010

Even though dispersion operations have been the object of several investigations, the importance of the different parameters and especially the physicochemical and surface properties are rarely treated. Dry particle coating can be used to create new generation materials. In such processes, host particles are mechanically coated with guest particles, without using solvents and subsequent drying, to create new functionalities or to improve initial characteristics. This study examines the surface properties of talc particles modified by dry coating with hydrophobic silica particles. Two parameters have been studied: the concentration of silica particles and the dry coating processing time. Both parameters allow modifications of the work of adhesion of talc particles with water, which is a characteristic of wettability. This change of wettability can consequently influence the dispersion rate of talc in water. © 2010 American Institute of Chemical Engineers AIChE J, 2011
Hydrogen generation from noncatalytic hydrothermolysis of ammonia borane for vehicle applications
Authors: Diwan Moiz , Hwang Hyun Tae , Al‐Kukhun Ahmad , Varma Arvind
Published: March 2010

Ammonia borane (AB) is a promising hydrogen storage material as it contains 19.6 wt % hydrogen. In this article, our recently developed hydrothermolysis approach to release hydrogen is studied over a wide range of AB concentrations (6–88 wt %), at pressure 14.7 and 200 psia, and temperature 85–135°C. It is shown that with increasing AB concentration up to 77 wt %, the H2 yield increases, and that the role of thermolysis, when compared with hydrolysis, increases. The maximum hydrogen storage capacity, obtained at 77 wt % AB and Treactor ∼ 85°C along with rapid kinetics, was 11.6 and 14.3 wt % at pressure 14.7 and 200 psia, respectively. To our knowledge, on a material basis, the AB hydrothermolysis process is the first one to provide such high hydrogen yield values at near PEM fuel cell operating temperatures without use of catalyst, and thus is promising for use in fuel cell‐based vehicle applications. © 2010 American Institute of Chemical Engineers AIChE J, 2011
Dynamic Transcriptional Changes of TIEG1 and TIEG2 During Mouse Tissue Development
Authors: Jiang Lei , Chen Yangchao , Chan Chu‐Yan , Lu Gang , Wang Hua , Li Ji‐Cheng , Kung Hsiang‐Fu
Published: March 2010

TGF‐β‐inducible early‐response gene (TIEG) is a family of primary response genes induced by TGF‐β, which are well recognized in regulating cellular proliferation and apoptosis. However, their expression profile has never been investigated during embryogenesis in different organs. In this study, we aimed to investigate the transcriptional level of both TIEG1 and TIEG2 during development in various mice organs, including the brain cortex, cerebellum and stem, brain striatum, muscle, heart, liver, kidney, and lung. Quantitative real‐time PCR was used to profile the change of transcriptional level of the two TIEG members in the mice tissues at six developmental stages. Taken together, the expression of TIEG1 and TIEG2 was specific in different organs yet varied with different developmental time points. Their dynamic changes were moderately consistent in most organs including the brain cortex, striatum, liver, kidney, and lung. However, their mRNA expression in both the heart and muscle was significantly different at all developmental stages, which might propose a compensation of functions in the TIEG family. Nevertheless, our data indicate that both the TIEG genes are essential in regulating the normal organ development and functioning in murine model, as their expressions were ubiquitous and tissue specific at various developmental stages. Anat Rec, 2010. © 2010 Wiley‐Liss, Inc.
Genetic deficiency of Syk protects mice from autoantibody‐induced arthritis
Authors: Jakus Zoltán , Simon Edina , Balázs Bálint , Mócsai Attila
Published: March 2010

Objective

The Syk tyrosine kinase plays an important role in diverse functions in hematopoietic lineage cells. Although previous in vitro and pharmacologic analyses suggested Syk to be a possible player in the development of autoimmune arthritis, no in vivo genetic studies addressing that issue have yet been reported. The aim of the present study was to test whether genetic deficiency of Syk affects autoantibody‐induced experimental arthritis in the K/BxN serum–transfer model.

Methods

Syk−/− bone marrow chimeras carrying a Syk‐deficient hematopoietic system were generated by transplanting Syk−/− fetal liver cells into lethally irradiated wild‐type recipients. After complete repopulation of the hematopoietic compartment, autoantibody‐mediated arthritis was induced by injection of arthritogenic K/BxN serum. Arthritis development was monitored by macroscopic and microscopic observation of the ankle joints, micro–computed tomography of bone morphology, as well as a joint function assay.

Results

Genetic deficiency of Syk in the hematopoietic compartment completely blocked the development of all macroscopic and microscopic signs of arthritis. The Syk−/− mutation also prevented the appearance of periarticular bone erosions. Finally, Syk−/− bone marrow chimeras were completely protected from arthritis‐induced loss of articular function.

Conclusion

Our results indicate that Syk is critically involved in the development of all clinically relevant aspects of autoantibody‐mediated K/BxN serum–transfer arthritis in experimental mice. These results provide the first in vivo genetic evidence of the role of Syk in the development of autoimmune arthritis.
META060 inhibits osteoclastogenesis and matrix metalloproteinases in vitro and reduces bone and cartilage degradation in a mouse model of rheumatoid arthritis
Authors: Konda Veera Reddy , Desai Anuradha , Darland Gary , Bland Jeffrey S. , Tripp Matthew L.
Published: March 2010

Objective

The multikinase inhibitor META060 has been shown to inhibit NF‐κB activation and expression of markers of inflammation. This study was undertaken to investigate the effect of META060 on biomarkers associated with bone and cartilage degradation in vitro and its antiinflammatory efficacy in vivo in both acute and chronic inflammation models.

Methods

Glycogen synthase kinase 3β (GSK3β)–dependent β‐catenin phosphorylation was evaluated in RAW 264.7 macrophages to assess kinase inhibition. The inhibition of osteoclastogenesis and tartrate‐resistant acid phosphatase (TRAP) activity was evaluated in RANKL‐treated RAW 264.7 cells. The inhibition of interleukin‐1β (IL‐1β)–mediated markers of inflammation was analyzed in human rheumatoid arthritis synovial fibroblasts (RASFs). Mice with carrageenan‐induced acute inflammation and collagen‐induced arthritis (CIA) were used to assess efficacy.

Results

META060 inhibited the activity of kinases (spleen tyrosine kinase [Syk], Bruton's tyrosine kinase [Btk], phosphatidylinositol 3‐kinase [PI 3‐kinase], and GSK3) associated with RA and inhibited β‐catenin phosphorylation. META060 inhibited osteoclastogenesis, as indicated by decreased transformation of RAW 264.7 cells to osteoclasts and reduced TRAP activity, and inhibited IL‐1β–activated prostaglandin E2, matrix metalloproteinase 3, IL‐6, IL‐8, and monocyte chemotactic protein 1 in RASFs. In mice with acute inflammation, oral administration of META060 reduced paw swelling similar to the effect of aspirin. In mice with CIA, META060 significantly reduced the arthritis index and decreased bone, joint, and cartilage degradation. Serum IL‐6 concentrations in these mice were inhibited in a dose‐dependent manner.

Conclusion

Our findings indicate that META060 reduces swelling in a model of acute inflammation and inhibits bone and cartilage destruction in a model of chronic inflammation. Its efficacy is associated with the inhibition of multiple protein kinases, including Syk, Btk, PI 3‐kinase, and GSK3. These results warrant further clinical testing of META060 for its therapeutic potential in the treatment of inflammatory diseases.
Markers of oxidative and nitrosative stress in systemic lupus erythematosus: Correlation with disease activity
Authors: Wang Gangduo , Pierangeli Silvia S. , Papalardo Elizabeth , Ansari G. A. S. , Khan M. Firoze
Published: March 2010

Objective

Free radical–mediated reactions have been implicated as contributors in a number of autoimmune diseases, including systemic lupus erythematosus (SLE). However, the potential for oxidative/nitrosative stress to elicit an autoimmune response or to contribute to disease pathogenesis, and thus be useful when determining a prognosis, remains largely unexplored in humans. This study was undertaken to investigate the status and contribution of oxidative/nitrosative stress in patients with SLE.

Methods

Sera from 72 SLE patients with varying levels of disease activity according to the SLE Disease Activity Index (SLEDAI) and 36 age‐ and sex‐matched healthy controls were evaluated for serum levels of oxidative/nitrosative stress markers, including antibodies to malondialdehyde (anti‐MDA) protein adducts and to 4‐hydroxynonenal (anti‐HNE) protein adducts, MDA/HNE protein adducts, superoxide dismutase (SOD), nitrotyrosine (NT), and inducible nitric oxide synthase (iNOS).

Results

Serum analysis showed significantly higher levels of both anti–MDA/anti–HNE protein adduct antibodies and MDA/HNE protein adducts in SLE patients compared with healthy controls. Interestingly, not only was there an increased number of subjects positive for anti‐MDA or anti‐HNE antibodies, but also the levels of both of these antibodies were statistically significantly higher among SLE patients whose SLEDAI scores were ≥6 as compared with SLE patients with lower SLEDAI scores (SLEDAI score <6). In addition, a significant correlation was observed between the levels of anti‐MDA or anti‐HNE antibodies and the SLEDAI score (r = 0.734 and r = 0.647, respectively), suggesting a possible causal relationship between these antibodies and SLE. Furthermore, sera from SLE patients had lower levels of SOD and higher levels of iNOS and NT compared with healthy control sera.

Conclusion

These findings support an association between oxidative/nitrosative stress and SLE. The stronger response observed in serum samples from patients with higher SLEDAI scores suggests that markers of oxidative/nitrosative stress may be useful in evaluating the progression of SLE and in elucidating the mechanisms of disease pathogenesis.
MicroRNA‐29, a key regulator of collagen expression in systemic sclerosis
Authors: Maurer Britta , Stanczyk Joanna , Jüngel Astrid , Akhmetshina Alfiya , Trenkmann Michelle , Brock Matthias , Kowal‐Bielecka Otylia , Gay Renate E. , Michel Beat A. , Distler Jörg H. W. , Gay Steffen , Distler Oliver
Published: March 2010

Objective

To investigate the role of microRNA (miRNA) as posttranscriptional regulators of profibrotic genes in systemic sclerosis (SSc).

Methods

MicroRNA, which target collagens, were identified by in silico analysis. Expression of miRNA‐29 (miR‐29) was determined by TaqMan real‐time polymerase chain reaction analysis of skin biopsy and fibroblast samples from SSc patients and healthy controls as well as in the mouse model of bleomycin‐induced skin fibrosis. Cells were transfected with precursor miRNA (pre‐miRNA)/anti‐miRNA of miR‐29 using Lipofectamine. Collagen gene expression was also studied in luciferase reporter gene assays. For stimulation, recombinant transforming growth factor β (TGFβ), platelet‐derived growth factor B (PDGF‐B), or interleukin‐4 (IL‐4) was used. The effects of inhibiting PDGF‐B and TGFβ signaling on the levels of miR‐29 were studied in vitro and in the bleomycin model.

Results

We found that miR‐29a was strongly down‐regulated in SSc fibroblasts and skin sections as compared with the healthy controls. Overexpression in SSc fibroblasts significantly decreased, and accordingly, knockdown in normal fibroblasts increased, the levels of messenger RNA and protein for type I and type III collagen. In the reporter gene assay, cotransfection with pre‐miR‐29a significantly decreased the relative luciferase activity, which suggests a direct regulation of collagen by miR‐29a. TGFβ, PDGF‐B, or IL‐4 reduced the levels of miR‐29a in normal fibroblasts to those seen in SSc fibroblasts. Similar to human SSc, the expression of miR‐29a was reduced in the bleomycin model of skin fibrosis. Inhibition of PDGF‐B and TGFβ pathways by treatment with imatinib restored the levels of miR‐29a in vitro and in the bleomycin model in vivo.

Conclusion

These data add the posttranscriptional regulation of collagens by miR‐29a as a novel aspect to the fibrogenesis of SSc and suggest miR‐29a as a potential therapeutic target.
Modulation of antigen expression in B‐cell precursor acute lymphoblastic leukemia during induction therapy is partly transient: Evidence for a drug‐induced regulatory phenomenon. Results of the AIEOP‐BFM‐ALL‐FLOW‐MRD‐Study Group
Authors: Dworzak Michael N. , Gaipa Giuseppe , Schumich Angela , Maglia Oscar , Ratei Richard , Veltroni Marinella , Husak Zvenyslava , Basso Giuseppe , Karawajew Leonid , Gadner Helmut , Biondi Andrea
Published: March 2010

Background: Changes of antigen expression on residual blast cells of acute lymphoblastic leukemia (ALL) occur during induction treatment. Many markers used for phenotyping and minimal residual disease (MRD) monitoring are affected. Glucocorticoid (GC)‐induced expression modulation has been causally suspected, however, subclone selection may also cause the phenomenon.

Methods: We investigated this by following the phenotypic evolution of leukemic cells with flow cytometry from diagnosis to four time points during and after GC containing chemotherapy in the 20 (of 360 consecutive) B‐cell precursor patients with ALL who had persistent MRD throughout.

Results: The early expression changes of CD10 and CD34 were reversible after stop of GC containing chemotherapy. Modulation of CD20 and CD45 occurred mostly during the GC phase, whereas CD11a also changed later on. Blast cells at diagnosis falling into gates designed according to “shifted” phenotypes from follow‐up did not form clusters and were frequently less numerous than later on.

Conclusions: Our data support the idea that drug‐induced modulation rather than selection causes the phenomenon. The good message for MRD assessment is that modulation is transient in at least two (CD10 and CD34) of the five prominent antigens investigated and reverts to initial aberrant patterns after stop of GC therapy, whereas CD20 expression gains new aberrations exploitable for MRD detection. © 2010 Clinical Cytometry Society
Identification of a distantcis‐regulatory element controlling pharyngeal arch‐specific expression of zebrafishgdf6a/radar
Authors: Reed Nykolaus P. , Mortlock Douglas P.
Published: March 2010

Skeletal formation is an essential and intricately regulated part of vertebrate development. Humans and mice deficient in growth and differentiation factor 6 (Gdf6) have numerous skeletal abnormalities, including joint fusions and cartilage reductions. The expression ofGdf6is dynamic and in part regulated by distant evolutionarily conservedcis‐regulatory elements.radar/gdf6ais a zebrafish ortholog ofGdf6and has an essential role in embryonic patterning. Here, we show thatradaris transcribed in the cells surrounding and between the developing cartilages of the ventral pharyngeal arches, similar to mouseGdf6. A 312 bp evolutionarily conserved region (ECR5), 122 kilobases downstream, drives expression in a pharyngeal arch‐specific manner similar to endogenousradar/gdf6a. Deletion analysis identified a 78 bp region within ECR5 that is essential for transgene activity. This work illustrates thatradaris regulated in the pharyngeal arches by a distant conserved element and suggestsradarhas similar functions in skeletal development in fish and mammals. Developmental Dynamics 239:1047–1060, 2010. © 2010 Wiley‐Liss, Inc.
Differential time course of FSH/FSH receptor complex endocytosis within sertoli and germ cells during rat testis development
Authors: Segretain Dominique , Gilleron Jérome , Carette Diane , Denizot Jean‐Pierre , Pointis Georges
Published: March 2010

Follicle‐stimulating hormone (FSH) is required for initiation and maintenance of spermatogenesis, a dynamic process of cell proliferation and maturation. By using FSH‐gold particles and pulse‐chase experiments, we analyzed the kinetics of FSH endocytosis in Sertoli and germ cells during development. Ultrastructural time‐dependent analysis demonstrates that FSH was first located on plasma membrane, before being accumulated within the endosomal compartment, in the early endosomes, identified by morphological criteria and Rab‐5 colocalization. Thereafter, FSH‐gold was routed to the degradation pathway. The FSH endocytosis kinetic was similar in Sertoli cells, spermatogonia and spermatocytes. However, quantitative analysis of gold particles revealed differences in the dynamic of FSH accumulation in the endosomes between immature and mature rats. This age‐dependent kinetic of FSH endocytosis, mostly detectable by ultrastructural analysis associated with quantitative data, argues for a potential new regulatory mechanism of the FSH signalling pathway that could occur during maturation of testicular cells. Developmental Dynamics 239:1113–1123, 2010. © 2010 Wiley‐Liss, Inc.
NTPDase1 governs P2X7‐dependent functions in murine macrophages
Authors: Lévesque Sébastien A. , Kukulski Filip , Enjyoji Keiichi , Robson Simon C. , Sévigny Jean
Published: March 2010

P2X7 receptor is an adenosine triphosphate (ATP)‐gated ion channel within the multiprotein inflammasome complex. Until now, little is known about regulation of P2X7 effector functions in macrophages. In this study, we show that nucleoside triphosphate diphosphohydrolase 1 (NTPDase1)/CD39 is the dominant ectonucleotidase expressed by murine peritoneal macrophages and that it regulates P2X7‐dependent responses in these cells. Macrophages isolated from NTPDase1‐null mice (Entpd1−/−) were devoid of all ADPase and most ATPase activities when compared with WT macrophages (Entpd1+/+). Entpd1−/− macrophages exposed to millimolar concentrations of ATP were more susceptible to cell death, released more IL‐1β and IL‐18 after TLR2 or TLR4 priming, and incorporated the fluorescent dye Yo‐Pro‐1 more efficiently (suggestive of increased pore formation) than Entpd1+/+ cells. Consistent with these observations, NTPDase1 regulated P2X7‐associated IL‐1β release after synthesis, and this process occurred independently of, and prior to, cytokine maturation by caspase‐1. NTPDase1 also inhibited IL‐1β release in vivo in the air pouch inflammatory model. Exudates of LPS‐injected Entpd1−/− mice had significantly higher IL‐1β levels when compared with Entpd1+/+ mice. Altogether, our studies suggest that NTPDase1/CD39 plays a key role in the control of P2X7‐dependent macrophage responses.
Influence of human cytomegalovirus infection on the NK cell receptor repertoire in children
Authors: Monsiváis‐Urenda Adriana , Noyola‐Cherpitel Daniel , Hernández‐Salinas Alba , García‐Sepúlveda Christian , Romo Neus , Baranda Lourdes , López‐Botet Miguel , González‐Amaro Roberto
Published: March 2010

Human cytomegalovirus (hCMV) infection is usually asymptomatic but may cause disease in immunocompromised hosts. It has been reported that hCMV infection may shape the NK cell receptor (NKR) repertoire in adult individuals, promoting a variable expansion of the CD94/NKG2C+ NK cell subset. We explored the possible relationship between this viral infection and the expression pattern of different NKR including CD94/NKG2C, CD94/NKG2A, immunoglobulin‐like transcript 2 (ILT2, CD85j), KIR2DL1/2DS1, KIR3DL1, and CD161 in peripheral blood lymphocytes from healthy children, seropositive (n=21) and seronegative (n=20) for hCMV. Consistent with previous observations in adults, a positive serology for hCMV was associated with increased numbers of NKG2C+ NK and T cells as well as with ILT2+ T lymphocytes. Moreover, the proportions of CD161+ and NKG2C+CD56−CD3− NK cells also tended to be increased in hCMV+ individuals. Excretion of the virus was associated with higher proportions of NKG2C+ NK cells. Altogether, these data reveal that hCMV may have a profound influence on the NKR repertoire in early childhood.
Interleukin‐4 downregulates CD127 expression and activity on human thymocytes and mature CD8+ T cells
Authors: Crawley Angela M. , Vranjkovic Agatha , Young Charlene , Angel Jonathan B.
Published: March 2010

Signaling via the IL‐7 receptor complex (IL‐7Rα/CD127 and IL‐2Rγ/CD132) is required for T‐cell development and survival. Decreased CD127 expression has been associated with persistent viral infections (e.g. HIV, HCV) and cancer. Many IL‐2Rγ‐sharing (γC) cytokines decrease CD127 expression on CD4+ and CD8+ T cells in mice (IL‐2, IL‐4, IL‐7, IL‐15) and in humans (IL‐2, IL‐7), suggesting a common function. IL‐4 is of particular interest as it is upregulated in HIV infection and in thyroid and colon cancers. The role of IL‐4 in regulating CD127 expression and IL‐7 activity in human thymocytes and mature CD8+ T cells is unknown and was therefore investigated. IL‐4 decreased CD127 expression on all thymocyte subsets tested and only on naïve (CD45RA+) CD8+ T cells, without altering membrane‐bound CD127 mRNA expression. Pre‐treatment of thymocytes or CD8+ T cells with IL‐4 inhibited IL‐7‐mediated phosphorylation of STAT5 and decreased proliferation of CD8+ T cells. By downregulating CD127 expression and signaling on developing thymocytes and CD8+ T cells, IL‐4 is a potential contributor to impaired CD8+ T‐cell function in some anti‐viral and anti‐tumor responses. These findings are of particular consequence to diseases such as HIV, HCV, RSV, measles and cancer, in which CD127 expression is decreased, IL‐7 activity is impaired and IL‐4 concentrations are elevated.
The NLRP3 inflammasome, a target for therapy in diverse disease states
Authors: Cook Graham P. , Savic Sinisa , Wittmann Miriam , McDermott Michael F.
Published: March 2010

A role for NLRP3 inflammasome in recurrent and chronic inflammation was initially described in a group of rare autoinflammatory conditions, termed cryopyrin‐associated periodic syndrome. Subsequently, inflammasomes have been implicated in the pathology of many common diseases, including cancer, gout and diabetes. Despite diverse pathologies, the central role of the inflammasome in innate defences and tumour elimination suggests common therapeutic approaches to reduce inflammation where appropriate.
The Drosophila PRR GNBP3 assembles effector complexes involved in antifungal defenses independently of its Toll‐pathway activation function
Authors: Matskevich Alexey A. , Quintin Jessica , Ferrandon Dominique
Published: March 2010

The Drosophila Toll‐signaling pathway controls the systemic antifungal host response. Gram‐negative binding protein 3 (GNBP3), a member of the β‐glucan recognition protein family senses fungal infections and activates this pathway. A second detection system perceives the activity of proteolytic fungal virulence factors and redundantly activates Toll. GNBP3hades mutant flies succumb more rapidly to Candida albicans and to entomopathogenic fungal infections than WT flies, despite normal triggering of the Toll pathway via the virulence detection system. These observations suggest that GNBP3 triggers antifungal defenses that are not dependent on activation of the Toll pathway. Here, we show that GNBP3 agglutinates fungal cells. Furthermore, it can activate melanization in a Toll‐independent manner. Melanization is likely to be an essential defense against some fungal infections given that the entomopathogenic fungus Beauveria bassiana inhibits the activity of the main melanization enzymes, the phenol oxidases. Finally, we show that GNBP3 assembles “attack complexes”, which comprise phenoloxidase and the necrotic serpin. We propose that Drosophila GNBP3 targets fungi immediately at the inception of the infection by bringing effector molecules in direct contact with the invading microorganisms.
New insights into the nature of autoinflammatory diseases from mice with Nlrp3 mutations
Authors: Meng Guangxun , Strober Warren
Published: March 2010

Mutations in the Nlrp3 (CIAS1, cryopyrin) gene are associated with cryopyrin‐associated periodic syndrome, autoinflammatory diseases characterized by excessive IL‐1 production and neutrophilia in blood and tissues. Recent studies with gene‐targeted mice expressing mutations homologous to those found in cryopyrin‐associated periodic syndrome patients have advanced the understanding of NLRP3‐associated autoinflammation. In this Viewpoint, we will discuss the mechanisms of NLRP3 inflammasome activation and its induction of Th17‐cell‐dominant immunologic responses.
Genetics of inflammasome‐associated disorders: A lesson in the guiding principals of inflammasome function
Authors: Rodrigue‐Gervais Ian Gaël , Saleh Maya
Published: March 2010

Human genetics research has had a great impact on the genesis of the inflammasome field and the treatment of certain inflammasomopathies. The identification of mutations causing rare autoinflammatory syndromes, reproductive wastage disorders and of single nucleotide polymorphisms influencing susceptibility to complex diseases such as vitiligo, sepsis, and Crohn's disease has not only led to the characterization of novel proteins involved in NOD‐like receptor‐coupled inflammatory signaling pathways but also to greater insights into pathogenic mechanisms.