4th meeting of the EU research network EUROME: From the identification of genes and cellular networks in murine models of arthritis to novel therapeutic intervention strategies in rheumatoid arthritis, London, UK, 9 March 2004

Rheumatoid arthritis (RA) is a common human disease with a prevalence of about 1% in most parts of the world. At the time of symptom onset it is difficult to predict the severity of subsequent disease course. After 2 years joint erosions are seen in most patients, and most patients become clinically disabled within 20 years. A recent meeting at the Kennedy Institute of Rheumatology (Imperial College, London) brought together representatives from several European centres of excellence, to discuss research funded by the EU Framework 5 Quality of Life Programme. This research network combines gene and protein expression profiling with different animal models of RA to identify cells, genes and pathways contributing to arthritis initiation, progression and chronicity. The studies discussed highlight the reality that collaboration between different research groups is the basis of groundbreaking research and, it is hoped, eventual new therapies for RA

Molecular responses to hypoxia in tumor cells

Highly aggressive, rapidly growing tumors are exposed to hypoxia or even anoxia which occurs as a consequence of inadequate blood supply. Both hypoxia and consecutive hypoxia/reoxygenation exert a variety of influences on tumor cell biology. Among these are activation of certain signal transduction pathways and gene regulatory mechanisms, induction of selection processes for gene mutations, tumor cell apoptosis and tumor angiogenesis. Most of these mechanisms contribute to tumor progression. Therefore, tissue hypoxia has been regarded as a central factor for tumor aggressiveness and metastasis. In this review, we summarize the current knowledge about the molecular mechanisms induced by tumor cell hypoxia with a special emphasis on intracellular signal transduction, gene regulation, angiogenesis and apoptosis. Interfering with these pathways might open perspectives for future innovative treatment of highly aggressive metastasizing tumors

Cytokines and Cytokine Profiles in Human Autoimmune Diseases and Animal Models of Autoimmunity

The precise pathomechanisms of human autoimmune diseases are still poorly understood. However, a deepened understanding of these is urgently needed to improve disease prevention and early detection and guide more specific treatment approaches. In recent years, many new genes and signalling pathways involved in autoimmunity with often overlapping patterns between different disease entities have been detected. Major contributions were made by experiments using DNA microarray technology, which has been used for the analysis of gene expression patterns in chronic inflammatory and autoimmune diseases, among which were rheumatoid arthritis, systemic lupus erythematosus, psoriasis, systemic sclerosis, multiple sclerosis, and type-1 diabetes. In systemic lupus erythematosus, a so-called interferon signature has been identified. In psoriasis, researchers found a particular immune signalling cluster. Moreover the identification of a new subset of inflammatory T cells, so-called Th17 T cells, secreting interleukin (IL)-17 as one of their major cytokines and the identification of the IL-23/IL-17 axis of inflammation regulation, have significantly improved our understanding of autoimmune diseases. Since a plethora of new treatment approaches using antibodies or small molecule inhibitors specifically targeting cytokines, cellular receptors, or signalling mechanisms has emerged in recent years, more individualized treatment for affected patients may be within reach in the future

Environmental Impact of High Altitudes on the Operation of PEM Fuel Cell Based UAS

Fuel cell is a device that converts the chemical energy in the reactants into the electrical energy after steps of sequential electrochemical processes with no significant impact on the environment. For high altitude long endurance (HALE) of unmanned aircraft system (UAS) where fuel cell operates as a prime source of power, the operation and performance of a PEM fuel cell at different level of altitudes is vitally important. In this paper, the impact of direct using extracted air from high altitudes atmosphere in order to feed the stack is investigated, and the governing equations of the supplied air and oxygen to the PEM fuel cell stack are developed. The impact of high altitudes upon the operation and the consumption of air are determined in order to maintain certain level of delivered power to the load. Also the implications associated with operating the PEM fuel cell stack at high altitudes and different technical solutions are proposed. Various modes of Integral, Proportional-Integral, and Proportional-Integral-Derivative controller are introduced and examined for different time setting responses in order to determine the most adequate trade-off choice between fast response and reactants consumption which provides the necessary optimization of the air consumption for the developed model of PEM fuel cell used for UAS operation

Evidence of a role for Th17 cells in the breach of immune tolerance in arthritis

Th17 cells are thought to play a pathogenic role in various autoimmune diseases. Cytokines secreted by Th17 cells like IL-17, IL-17F and IL-22 have the capacity to mediate a massive inflammatory response. These proinflammatroy cytokines are likely to mediate the pathogenic potential of Th17 cells. Recent evidence suggests a role for Th17 cells in the breach of immune tolerance. This might shed some new light on the pathogenic role of Th17 cells in autoimmunity

14-3-3σ gene silencing during melanoma progression and its role in cell cycle control and cellular senescence

<p>Abstract</p> <p>Background</p> <p>The family of 14-3-3 proteins plays an important role in cancer biology by interfering with intracellular signalling pathways and cell cycle checkpoints. The 14-3-3σ isoform acts as a tumor suppressor and is often inactivated during tumor development.</p> <p>Results</p> <p>Here, we demonstrate enhanced CpG methylation of the 14-3-3σ gene in lymph node and cutaneous melanoma metastases compared with primary tumors, associated with dramatically reduced mRNA expression. In line with this, treatment of different metastatic melanoma cell lines with 5-aza-2'-deoxycytidine (5-Aza-CdR), a potent inhibitor of cytosine methylation, significantly induces 14-3-3σ protein expression. Additional treatment with histone deacetylase inhibitor 4-phenylbutyric acid (Pba) further enhances 14-3-3σ expression. Induction of 14-3-3σ expression by 5-Aza-CdR/Pba treatment leads to almost complete inhibition of cell proliferation, with cells predominantly arrested in G2-M. The antiproliferative effect of 5-Aza-CdR/Pba was reversed in 14-3-3σ knockdown cells. Similarly, melanoma cell lines stably overexpressing 14-3-3σ show dramatically reduced cell proliferation rates. Moreover, synchronous 14-3-3σ stably overexpressing cells do not progress through cell cycle, but display a permanent increase in the population of 4<it>n </it>DNA containing cells. Interestingly, overexpression of 14-3-3σ induces senescence of melanoma cells and is involved in melanoma cell senescence under genotoxic stress. Finally, 14-3-3σ knockdown supports migratory capacity of melanoma cells <it>in vitro</it>, while 14-3-3σ overexpression has opposing effects.</p> <p>Conclusion</p> <p>Taken together, the present report indicates that epigenetic silencing of 14-3-3σ might contribute to tumor progression in malignant melanoma via loss of cell cycle control, impaired cellular senescence program and support of migratory capacity.</p

EXPLORING THE INAR MODEL ON HEAVY TAILED TIME SERIES DATA WITH OUTLIERS

Count data are intrinsically measures of event frequency; it is clear that there is an intrinsic relationship with recurring time to event. Events are typically tallied within time intervals for practical and convenient reasons. The existence of outliers is one issue that prevents count data from being stationary in time series analysis; this has an impact on the effectiveness of fitting several common stationary models to the count data collected over time. Thus, the purpose of this study was to examine how well the Integer Valued Autoregressive (INAR) model performed while modeling count data that included outliers. While this model has been studied for count time series data, it has not been studied for varying degrees of outliers. A monte-carlo simulation was carried out to select the best INAR(p), where p=1,2,3 and 4 on data with 10%, 20% and 30% outliers at different sample sizes. The INAR (4) has the best fit across the sample sizes at the larger percentages of outliers while INAR (3) at the lowest percentage with smallest information criteria of assessment and they are therefore recommended for such modeling.

Evaluation of The Living Escherichia coli-O78 Deleted aroA Vaccine Against Homologous and Heterologous E. coli Challenge in Broiler Chickens

To determine whether the immunization using commercially available living Escherichia coli-O78 aroA deleted vaccine (Poulvac®E. coli) is protective against APEC challenges or not. Ninety chicks were divided into six groups (15 birds/each); two groups were vaccinated at day 1 by spray and drinking routes then challenged intratracheally with homologous E. coli O78 at day 21, the other two groups were similar to the previously mentioned groups but challenged with heterologous E. coli O1 in parallel with the four challenged-vaccinated groups there were two positive control (challenged-not vaccinated) groups; one challenged with O78 and the other one with O1 at day 21 using intratacheal route. The best obtained results were recorded to the vaccinated-challenged group with the homologous strain and vaccinated by spraying method which exhibited decreases in organ lesion scores in comparison to the other groups (non-vaccinated challenged chickens and groups of chickens either homologous challenged-vaccinated through drinking water or heterologous challenged-vaccinated groups). These findings suggest that vaccine is a suitable for minimizing lesion scores against homologous challenge using spraying method that could lead to minimizing the time for treatment and cases of condemnation in processing plants

Light and Electron Microscopical Studies on the Hyalocytes of Turkey (Meleagris Gallopavo)

The present study aimed to investigate the light and electron microscopical structure of the hyalocytes in turkey. This study was applied on a total number of 15 (10 males and 5 females) clinically healthy turkeys of Bronze black species, collected from a local farm in Assiut Governorate, Egypt. For sampling and fixation, 30 turkey's eyeballs were enucleated and subjected to study. The hyalocytes appeared as large cell with different shapes (rounded, oval or elliptical). They located within ambushes found along the outer surface of the retino-pecteneal membrane. In these cells, present numerous cytoplasmic vacuoles and large oval nucleus located near the internal part of the cell. There were many cytoplasmic processes that joined each other as a fine meshwork enclosing several vesicles or parts of foreign materials along the external portion of the cell. On the internal or deep surface of the cell present numerous filopodia, which extended to occupy the depressions found on the outer surface of the retino-pecteneal membrane. The presence of ingested foreign materials and the appearance of filopodia in a moving condition along the internal surface of the cell insure that hyalocytes are considered highly active phagocytic cells

Combining global genome and transcriptome approaches to identify the candidate genes of small-effect quantitative trait loci in collagen-induced arthritis

Quantitative traits such as complex diseases are controlled by many small-effect genes that are difficult to identify. Here we present a novel strategy to identify the candidate genes for small-effect quantitative trait loci (QTL) in collagen induced arthritis (CIA) using global genome and transcriptome approaches. First, we performed genome linkage analysis in F2 progeny of the CIA susceptible and resistant strains to search for small-effect QTL. Second, we detected gene expression patterns of both strains during CIA. The candidate genes were identified using three criteria: they are located in a genomic region linked to CIA; they are disease-specific differentially expressed during CIA; and they are strain-specific differentially expressed regarding the two parental strains. Eight small-effect QTL controlling CIA severity were identified. Of 22,000 screened genes, 117 were both strain-specific and disease-specific differentially expressed during CIA. Of these 117 genes, 21 were located inside the support intervals of the 8 small-effect QTL and thus were considered as candidate genes