156 research outputs found
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Systems analysis of inflammatory bowel disease based on comprehensive gene information
<p>Abstract</p> <p>Background</p> <p>The rise of systems biology and availability of highly curated gene and molecular information resources has promoted a comprehensive approach to study disease as the cumulative deleterious function of a collection of individual genes and networks of molecules acting in concert. These "human disease networks" (HDN) have revealed novel candidate genes and pharmaceutical targets for many diseases and identified fundamental HDN features conserved across diseases. A network-based analysis is particularly vital for a study on polygenic diseases where many interactions between molecules should be simultaneously examined and elucidated. We employ a new knowledge driven HDN gene and molecular database systems approach to analyze Inflammatory Bowel Disease (IBD), whose pathogenesis remains largely unknown.</p> <p>Methods and Results</p> <p>Based on drug indications for IBD, we determined sibling diseases of mild and severe states of IBD. Approximately 1,000 genes associated with the sibling diseases were retrieved from four databases. After ranking the genes by the frequency of records in the databases, we obtained 250 and 253 genes highly associated with the mild and severe IBD states, respectively. We then calculated functional similarities of these genes with known drug targets and examined and presented their interactions as PPI networks.</p> <p>Conclusions</p> <p>The results demonstrate that this knowledge-based systems approach, predicated on functionally similar genes important to sibling diseases is an effective method to identify important components of the IBD human disease network. Our approach elucidates a previously unknown biological distinction between mild and severe IBD states.</p
Increased Susceptibility to LPS-induced Endotoxin Shock in Secretory Leukoprotease Inhibitor (SLPI)-deficient Mice
Secretory leukoprotease inhibitor (SLPI) protects tissue against the destructive action of neutrophil elastase at the site of inflammation. Recent studies on new functions of SLPI have demonstrated that SLPI may play a larger role in innate immunity than merely as a protease inhibitor. To clarify the functions of SLPI in bacterial infections, we generated SLPI-deficient mice (SLPI−/− mice) and analyzed their response to experimental endotoxin shock induced by lipopolysaccharide (LPS). SLPI−/− mice showed a higher mortality from endotoxin shock than did wild type mice. This may be explained in part by our observation that SLPI−/− macro-phages show higher interleukin 6 and high-mobility group (HMG)-1 production and nuclear factor κB activities after LPS treatment than do SLPI+/+ macrophages. SLPI also affects B cell function. SLPI−/− B cells show more proliferation and IgM production after LPS treatment than SLPI+/+ B cells. Our results suggest that SLPI attenuates excessive inflammatory responses and thus assures balanced functioning of innate immunity
Using spin to understand the formation of LIGO's black holes
With the detection of four candidate binary black hole (BBH) mergers by the
Advanced LIGO detectors thus far, it is becoming possible to constrain the
properties of the BBH merger population in order to better understand the
formation of these systems. Black hole (BH) spin orientations are one of the
cleanest discriminators of formation history, with BHs in dynamically formed
binaries in dense stellar environments expected to have spins distributed
isotropically, in contrast to isolated populations where stellar evolution is
expected to induce BH spins preferentially aligned with the orbital angular
momentum. In this work we propose a simple, model-agnostic approach to
characterizing the spin properties of LIGO's BBH population. Using measurements
of the effective spin of the binaries, which is LIGO's best constrained spin
parameter, we introduce a simple parameter to quantify the fraction of the
population that is isotropically distributed, regardless of the spin magnitude
distribution of the population. Once the orientation characteristics of the
population have been determined, we show how measurements of effective spin can
be used to directly constrain the underlying BH spin magnitude distribution.
Although we find that the majority of the current effective spin measurements
are too small to be informative, with LIGO's four BBH candidates we find a
slight preference for an underlying population with aligned spins over one with
isotropic spins (with an odds ratio of 1.1). We argue that it will be possible
to distinguish symmetric and anti-symmetric populations at high confidence with
tens of additional detections, although mixed populations may take
significantly more detections to disentangle. We also derive preliminary spin
magnitude distributions for LIGO's black holes, under the assumption of aligned
or isotropic populations
The Molecule Role Ontology: An Ontology for Annotation of Signal Transduction Pathway Molecules in the Scientific Literature
In general, it is not easy to specify a single sequence identity for each molecule name
that appears in a pathway in the scientific literature. A molecule name may stand
for concepts of various granularities, from concrete objects such as H-Ras and ERK1
to abstract concepts or categories such as Ras and MAPK. Typically, the relations
among molecule names derive a hierarchical structure; without a proper way to
handle this knowledge, it becomes ever more difficult to develop a reliable pathway
database. This paper describes an ontology that is designed to annotate molecules
in the scientific literature on signal transduction pathways
Epigenetic modulation of Fgf21 in the perinatal mouse liver ameliorates diet-induced obesity in adulthood
The nutritional environment to which animals are exposed in early life can lead to epigenetic changes in the genome that influence the risk of obesity in later life. Here, we demonstrate that the fibroblast growth factor-21 gene (Fgf21) is subject to peroxisome proliferator-activated receptor (PPAR) α–dependent DNA demethylation in the liver during the postnatal period. Reductions in Fgf21 methylation can be enhanced via pharmacologic activation of PPARα during the suckling period. We also reveal that the DNA methylation status of Fgf21, once established in early life, is relatively stable and persists into adulthood. Reduced DNA methylation is associated with enhanced induction of hepatic FGF21 expression after PPARα activation, which may partly explain the attenuation of diet-induced obesity in adulthood. We propose that Fgf21 methylation represents a form of epigenetic memory that persists into adulthood, and it may have a role in the developmental programming of obesity
Increased Systemic Glucose Tolerance with Increased Muscle Glucose Uptake in Transgenic Mice Overexpressing RXRγ in Skeletal Muscle
BACKGROUND: Retinoid X receptor (RXR) γ is a nuclear receptor-type transcription factor expressed mostly in skeletal muscle, and regulated by nutritional conditions. Previously, we established transgenic mice overexpressing RXRγ in skeletal muscle (RXRγ mice), which showed lower blood glucose than the control mice. Here we investigated their glucose metabolism. METHODOLOGY/PRINCIPAL FINDINGS: RXRγ mice were subjected to glucose and insulin tolerance tests, and glucose transporter expression levels, hyperinsulinemic-euglycemic clamp and glucose uptake were analyzed. Microarray and bioinformatics analyses were done. The glucose tolerance test revealed higher glucose disposal in RXRγ mice than in control mice, but insulin tolerance test revealed no difference in the insulin-induced hypoglycemic response. In the hyperinsulinemic-euglycemic clamp study, the basal glucose disposal rate was higher in RXRγ mice than in control mice, indicating an insulin-independent increase in glucose uptake. There was no difference in the rate of glucose infusion needed to maintain euglycemia (glucose infusion rate) between the RXRγ and control mice, which is consistent with the result of the insulin tolerance test. Skeletal muscle from RXRγ mice showed increased Glut1 expression, with increased glucose uptake, in an insulin-independent manner. Moreover, we performed in vivo luciferase reporter analysis using Glut1 promoter (Glut1-Luc). Combination of RXRγ and PPARδ resulted in an increase in Glut1-Luc activity in skeletal muscle in vivo. Microarray data showed that RXRγ overexpression increased a diverse set of genes, including glucose metabolism genes, whose promoter contained putative PPAR-binding motifs. CONCLUSIONS/SIGNIFICANCE: Systemic glucose metabolism was increased in transgenic mice overexpressing RXRγ. The enhanced glucose tolerance in RXRγ mice may be mediated at least in part by increased Glut1 in skeletal muscle. These results show the importance of skeletal muscle gene regulation in systemic glucose metabolism. Increasing RXRγ expression may be a novel therapeutic strategy against type 2 diabetes
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