Country-specific birth weight and length in type 1 diabetes high-risk HLA genotypes in combination with prenatal characteristics

Objective:To examine the relationship between high-risk human leukocyte antigen (HLA) genotypes for type 1 diabetes and birth size in combination with prenatal characteristics in different countries.Study Design:Four high-risk HLA genotypes were enrolled in the Environmental determinants of Diabetes in the Young study newborn babies from the general population in Finland, Germany, Sweden and the United States. Stepwise regression analyses were used to adjust for country, parental physical characteristics and environmental factors during pregnancy.Result:Regression analyses did not reveal differences in birth size between the four type 1 diabetes high-risk HLA genotypes. Compared with DQ 4/8 in each country, (1) DQ 2/2 children were heavier in the United States (P=0.028) mostly explained however, by parental weight; (2) DQ 2/8 (P=0.023) and DQ 8/8 (P=0.046) children were longer in Sweden independent of parents height and as well as (3) in the United States for DQ 2/8 (P=0.023), but again dependent on parental height.Conclusion:Children born with type 1 diabetes high-risk HLA genotypes have comparable birth size. Longitudinal follow-up of these children should reveal whether birth size differences between countries contribute to the risk for islet autoimmunity and type 1 diabetes.Journal of Perinatology advance online publication, 28 April 2011; doi:10.1038/jp.2011.26

Swarming populations of Salmonella represent a unique physiological state coupled to multiple mechanisms of antibiotic resistance

Salmonella enterica serovar Typhimurium is capable of swarming over semi-solid surfaces. Although its swarming behavior shares many readily observable similarities with other swarming bacteria, the phenomenon remains somewhat of an enigma in this bacterium since some attributes skew away from the better characterized systems. Swarming is quite distinct from the classic swimming motility, as there is a prerequisite for cells to first undergo a morphological transformation into swarmer cells. In some organisms, swarming is controlled by quorum sensing, and in others, swarming has been shown to be coupled to increased expression of important virulence factors. Swarming in serovar Typhimurium is coupled to elevated resistance to a wide variety of structurally and functionally distinct classes of antimicrobial compounds. As serovar Typhimurium differentiates into swarm cells, the pmrHFIJKLM operon is up-regulated, resulting in a more positively charged LPS core. Furthermore, as swarm cells begin to de-differentiate, the pmr operon expression is down-regulated, rapidly reaching the levels observed in swim cells. This is one potential mechanism which confers swarm cells increased resistance to antibiotics such as the cationic antimicrobial peptides. However, additional mechanisms are likely associated with the cells in the swarm state that confer elevated resistance to such a broad spectrum of antimicrobial agents

Pathway analysis comparison using Crohn's disease genome wide association studies

<p>Abstract</p> <p>Background</p> <p>The use of biological annotation such as genes and pathways in the analysis of gene expression data has aided the identification of genes for follow-up studies and suggested functional information to uncharacterized genes. Several studies have applied similar methods to genome wide association studies and identified a number of disease related pathways. However, many questions remain on how to best approach this problem, such as whether there is a need to obtain a score to summarize association evidence at the gene level, and whether a pathway, dominated by just a few highly significant genes, is of interest.</p> <p>Methods</p> <p>We evaluated the performance of two pathway-based methods (Random Set, and Binomial approximation to the hypergeometric test) based on their applications to three data sets of Crohn's disease. We consider both the disease status as a phenotype as well as the residuals after conditioning on IL23R, a known Crohn's related gene, as a phenotype.</p> <p>Results</p> <p>Our results show that Random Set method has the most power to identify disease related pathways. We confirm previously reported disease related pathways and provide evidence for IL-2 Receptor Beta Chain in T cell Activation and IL-9 signaling as Crohn's disease associated pathways.</p> <p>Conclusions</p> <p>Our results highlight the need to apply powerful gene score methods prior to pathway enrichment tests, and that controlling for genes that attain genome wide significance enable further biological insight.</p

Use of Data-Biased Random Walks on Graphs for the Retrieval of Context-Specific Networks from Genomic Data

Extracting network-based functional relationships within genomic datasets is an important challenge in the computational analysis of large-scale data. Although many methods, both public and commercial, have been developed, the problem of identifying networks of interactions that are most relevant to the given input data still remains an open issue. Here, we have leveraged the method of random walks on graphs as a powerful platform for scoring network components based on simultaneous assessment of the experimental data as well as local network connectivity. Using this method, NetWalk, we can calculate distribution of Edge Flux values associated with each interaction in the network, which reflects the relevance of interactions based on the experimental data. We show that network-based analyses of genomic data are simpler and more accurate using NetWalk than with some of the currently employed methods. We also present NetWalk analysis of microarray gene expression data from MCF7 cells exposed to different doses of doxorubicin, which reveals a switch-like pattern in the p53 regulated network in cell cycle arrest and apoptosis. Our analyses demonstrate the use of NetWalk as a valuable tool in generating high-confidence hypotheses from high-content genomic data

Predictors of long-term stability of maxillary dental arch dimensions in patients treated with a transpalatal arch followed by fixed appliances

Background: The aim of this retrospective study was to identify which dental and/or cephalometric variables were predictors of long-term maxillary dental arch stability in patients treated with a transpalatal arch (TPA) during the mixed dentition phase followed by full fixed appliances in the permanent dentition. Methods: Thirty-six patients, treated with TPA followed up by full fixed appliances, were divided into stable and relapse groups based on the long-term presence or not of relapse. Intercuspid, interpremolar and intermolar widths, arch length and perimeter, crowding, and upper incisor proclination were evaluated before treatment (T0), post-TPA treatment (T1), post-fixed appliance treatment (T2), and a minimum of 3 years after full fixed appliances’ removal (T3). A binary logistic regression was performed thereafter to evaluate the impact of the dental arch and cephalometric measurements at T1 and the changes between T0 and T1 as predictive variables for relapse at T3. Results: The proposed model explained 42.7 % of the variance in treatment stability and correctly classified 72.2 % of the sample. Of the seven predictive variables, only upper anterior crowding (p = 0.029) was statistically significant. For every millimeter of decreased crowding at T1 (after TPA treatment/before starting the fixed orthodontic treatment), there was an increase of 3.57 times in the odds of having stability. Conclusions: The best predictor of relapse was maxillary crowding before treatment. The odds of relapse increase by 3.6 times for every millimeter of crowding at baseline

The Aedes aegypti Toll Pathway Controls Dengue Virus Infection

Aedes aegypti, the mosquito vector of dengue viruses, utilizes its innate immune system to ward off a variety of pathogens, some of which can cause disease in humans. To date, the features of insects' innate immune defenses against viruses have mainly been studied in the fruit fly Drosophila melanogaster, which appears to utilize different immune pathways against different types of viruses, in addition to an RNA interference–based defense system. We have used the recently released whole-genome sequence of the Ae. aegypti mosquito, in combination with high-throughput gene expression and RNA interference (RNAi)-based reverse genetic analyses, to characterize its response to dengue virus infection in different body compartments. We have further addressed the impact of the mosquito's endogenous microbial flora on virus infection. Our findings indicate a significant role for the Toll pathway in regulating resistance to dengue virus, as indicated by an infection-responsive regulation and functional assessment of several Toll pathway–associated genes. We have also shown that the mosquito's natural microbiota play a role in modulating the dengue virus infection, possibly through basal-level stimulation of the Toll immune pathway

Distinct Mechanisms Underlying Tolerance to Intermittent and Constant Hypoxia in Drosophila melanogaster

BACKGROUND: Constant hypoxia (CH) and intermittent hypoxia (IH) occur during several pathological conditions such as asthma and obstructive sleep apnea. Our research is focused on understanding the molecular mechanisms that lead to injury or adaptation to hypoxic stress using Drosophila as a model system. Our current genome-wide study is designed to investigate gene expression changes and identify protective mechanism(s) in D. melanogaster after exposure to severe (1% O(2)) intermittent or constant hypoxia. METHODOLOGY/PRINCIPAL FINDINGS: Our microarray analysis has identified multiple gene families that are up- or down-regulated in response to acute CH or IH. We observed distinct responses to IH and CH in gene expression that varied in the number of genes and type of gene families. We then studied the role of candidate genes (up-or down-regulated) in hypoxia tolerance (adult survival) for longer periods (CH-7 days, IH-10 days) under severe CH or IH. Heat shock proteins up-regulation (specifically Hsp23 and Hsp70) led to a significant increase in adult survival (as compared to controls) of P-element lines during CH. In contrast, during IH treatment the up-regulation of Mdr49 and l(2)08717 genes (P-element lines) provided survival advantage over controls. This suggests that the increased transcript levels following treatment with either paradigm play an important role in tolerance to severe hypoxia. Furthermore, by over-expressing Hsp70 in specific tissues, we found that up-regulation of Hsp70 in heart and brain play critical role in tolerance to CH in flies. CONCLUSIONS/SIGNIFICANCE: We observed that the gene expression response to IH or CH is specific and paradigm-dependent. We have identified several genes Hsp23, Hsp70, CG1600, l(2)08717 and Mdr49 that play an important role in hypoxia tolerance whether it is in CH or IH. These data provide further clues about the mechanisms by which IH or CH lead to cell injury and morbidity or adaptation and survival

Purinergic signalling and immune cells

This review article provides a historical perspective on the role of purinergic signalling in the regulation of various subsets of immune cells from early discoveries to current understanding. It is now recognised that adenosine 5'-triphosphate (ATP) and other nucleotides are released from cells following stress or injury. They can act on virtually all subsets of immune cells through a spectrum of P2X ligand-gated ion channels and G protein-coupled P2Y receptors. Furthermore, ATP is rapidly degraded into adenosine by ectonucleotidases such as CD39 and CD73, and adenosine exerts additional regulatory effects through its own receptors. The resulting effect ranges from stimulation to tolerance depending on the amount and time courses of nucleotides released, and the balance between ATP and adenosine. This review identifies the various receptors involved in the different subsets of immune cells and their effects on the function of these cells